Oxoazetidine derivatives, process for the preparation thereof and use thereof in human medicine and in cosmetics

ABSTRACT

The present invention relates to novel compounds derived from oxoazetidine corresponding to general formula (I) to the compositions containing same, to the process for preparation thereof and to the use thereof in pharmaceutical or cosmetic compositions.

The invention relates to novel compounds as products that modulate oneor more melanocortin receptor(s). It also relates to the process for thepreparation thereof and to the therapeutic use thereof.

Melanocortins make up the family of regulatory peptides which aresynthesized by post-translational processing of the hormoneproopiomelanocortin (POMC—131 amino acids long). POMC results in theproduction of 3 classes of hormones, melanocortins, the hormoneadrenocorticotropin and various endorphins, such as, for example,ligotropin (Cone, et al., Recent Prog. Horm. Res., 51:287-317, (1996);Cone et al., Ann. N.Y. Acad. Sd., 31:342-363 (1993)).

Melanocortin receptors (MCRs) form part of the 7-transmembrane domainGPCR superfamily. To date, 5 receptor subtypes, MC1-5R, have beenidentified in mammals. An endogenous group of peptides binds to MCRswith agonist or antagonist effects, such as melanocyte-stimulatinghormones (MSH), adrenocorticotropic hormone (ACTH), and Agouti proteinsand derivatives thereof. One exception, however, is the MC2R receptor,which binds only with ACTH (Major pharmacological distinction of theACTH receptor from other melanocortin receptors, Schioth et al. Lifesciences (1996), 59(10), 797-801).

MCRs have varied roles at the physiological level. MC1R regulatesmelanin formation in the skin, and has a role in immune systemregulation. MC2R regulates corticosteroid production at the level of theadrenal glands. The MC3R and MC4R receptors play a role in the controlof food intake and sexual behaviour. MC5R is involved in exocrine glandregulation (Wikberg, Jarl E. S., Melanocortin receptors: perspectivesfor novel drugs. European Journal of Pharmacology (1999), 375(1-3)295-310. Wikberg, Jarl E. S., Melanocortin receptors: new opportunitiesin drug discovery. Expert Opinion on Therapeutic Patents (2001), 11(1),61-76).

The potential use of MCRs as a target for medicaments intended to treatsignificant pathological compositions such as obesity, diabetes,inflammatory conditions and sexual dysfunction creates a need forcompounds which show great specificity with respect to a particularsubtype. However, the modelling of medicaments that are selective forslightly different receptor subtypes is a difficult task that would besimplified if detailed knowledge of the determinants of theligand-receptor interaction was available.

The Applicant has now discovered, unexpectedly and surprisingly, thatnovel compounds of general formula (I) as defined hereinafter exhibitvery good activity on melanocortin receptors, and in particular certaincompounds are highly selective for MC1R.

It has been demonstrated in particular that MC1R is one of the keyproteins in the regulation of melanin synthesis in melanocytes.

MC1R is expressed in melanocytes and is involved in skin pigmentation,the colouration of animal fur and melanocyte functions. Melanocortinscan thus be used to treat hypopigmentary and hyperpigmentary disorders.MC1R gene polymorphism data have been associated with the auburn hairphenotype and with malignant and non-malignant skin cancers (Xu X et alNat Genet 1996; 14: 384; Van Der Velden P A et al Am J Hum Gent 2001;69; 774-779; Valverde P et al Hum Mol Genet 1996; 5; 1663-1666; SchiothH B Biochem Biophys Res Commun 1999; 260: 488-491; Scott M C et al JCell Sci 2002; 115; 2349-2355). Thus, a link exists between MC1R andmelanoma; as a result, MC1R may be important in the prevention andtreatment of certain forms of skin cancer (Stockfleth E et al RecentResults Cancer Res 2002; 160; 259-268; Stander et al Exp Dermatol 2002;11: 42-51). MC1R is also expressed in macrophages and monocytes (Star etal Proc. Natl. Acad. Sci. USA 92; 8016-8020; Hartmeyer et al J. Immunol.159; 1930-1937), neutrophils (Catania et al Peptides 17; 675-679),endothelial cells (Hartmeyer et al J. Immunol. 159; 1930-1937), gliomacells and astrocytes (Wong et al Neuroimmunomodulation 4, 37-41),fibroblasts (Boston and Cone, Endocrinology 137, 2043-2050) andkeratinocytes (Luger et al J. Invest Dermatol. Symp. Proc. 2, 87-93).The localization of MC1R in these cells is associated with the abilityof MSH-derived peptides to inhibit inflammatory processes. Specifically,α-MSH has shown a strong inhibition of inflammation in chronic models ofintestinal inflammation, of arthritis, of ischaemia, of contacthypersensitivity and of dermatitis, and is also capable of inducingtolerance to haptens (Ceriana et al Neuroimmunomodulation 1, 28-32;Chiao et al. Clin. Invest. 99, 1165-1172; Huh and Lipton Neurosurgery40, 132-139; Luger et al. J. Invest Dermatol. Symp. Proc. 2, 87-93;Rajora et al Peptides 18, 381-385; J. Neurosci. 17, 2181-2196; Lipton etal. Neuroimmunomodulation 5, 178-183). Melanocortins can thus be used totreat inflammatory disorders and immune disorders. It has been suggestedthat the MC1R signalling pathway plays a role in the perception of painand that functional variations in MC1R are associated with a high paintolerance (Mogil et al J Med Genet. 2005 July; 42(7): 583-7).

A strong correlation exists between human hair colour and MC1R variants(Valverde et al Nat Genet. 1995 November; 11(3): 328-30). Functionalvariations in MC1R are associated with the auburn hair colour.

It is also known that the sebaceous gland expresses both MC1R(Ganceviciene et al Exp Dermatol. 2007 July; 16(7): 547-52) and MC5R(Zhang et al Peptides. 2006 February; 27(2): 413-20). It has also beenreported that MC1R is overexpressed in the sebaceous gland in the caseof acne.

These compounds find uses in human medicine, in particular indermatology, and in the cosmetics field.

Among the oxoazetidine derivatives already known, some have beendescribed as having antibacterial properties (WO9709328, WO04045616,WO04087697), antiviral properties as CCR5 antagonists (WO04055016,WO08034731) and analgesic properties (Journal of Medicinal Chemistry(1968), 11, 466-470).

Patent WO9810653 discloses certain piperidine, pyrrolidine andhexahydro-1H-azepin compounds for promoting the synthesis of growthhormone in humans and animals.

Patents WO9635713 and WO9638471 disclose certain dipeptides forstimulating growth hormone synthesis.

The publication in the Journal of Medicinal Chemistry (2003), 46,1123-1126 describes the “discovery of tyrosine-based potent andselective MC1R receptor small-molecule agonists with anti-inflammatoryproperties”.

Patents WO02070511, WO02079146 and WO02069905 claim the use of compoundsas modulators of melanocortin receptors, more particularly MC1R andMC4R.

Now, the Applicant has found, unexpectedly and surprisingly, thatcertain compounds of formula (I), which are the subject of the presentinvention, are modulators of one or more melanocortin receptors and, inparticular, some compounds are highly selective for MC1R.

Thus, the present invention relates to compounds of general formula (I)below:

in which:

R1 represents an aryl, a substituted aryl or a cycloalkyl;

R2 represents a hydrogen atom, a hydroxyl, a lower alkyl, a substitutedlower alkyl, a higher alkyl, a substituted higher alkyl, a cycloalkyl, acycloalkylalkyl, a lower alkoxy, a substituted lower alkoxy, a higheralkoxy, a substituted higher alkoxy, a cycloalkylalkoxy, or an acyloxy;

R3 represents an aralkyl or a substituted aralkyl;

R4 represents a heteroalkyl, a substituted heteroaralkyl, a heteroalkylor a substituted heteroalkyl;

R5 represents a hydrogen atom, a hydroxyl, an amino, an acylamino or asulphonamide; and also the corresponding salts and enantiomers of thecompounds of general formula (I).

Among the addition salts of the compounds of general formula (I) with apharmaceutically acceptable acid, mention may preferably be made of thesalts with an organic acid or with an inorganic acid.

Suitable inorganic acids are, for example, hydrohalic acids such ashydrochloric acid or hydrobromic acid, sulphuric acid, or nitric acid.

Suitable organic acids are, for example, picric acid, methanesulphonicacid, ethanesulphonic acid, para-toluenesulphonic acid, citric acid,oxalic acid or tartaric acid.

The compounds of general formula (I) may also exist in the form ofhydrates or of solvates with water or with a solvent.

Appropriate solvents for forming solvates or hydrates are, for example,alcohols such as ethanol or isopropanol, or water.

According to the present invention, the term “aryl” denotes anunsubstituted phenyl or naphthyl.

According to the present invention, the term “substituted aryl” denotesa phenyl or a naphthyl substituted with one or more groups of atomschosen from an alkyl, an alkoxy, a halogen, a hydroxyl, a cyano, atrifluoromethyl and a nitro.

According to the present invention, the term “cycloalkyl” denotes acyclic, saturated hydrocarbon-based chain containing from 3 to 7 carbonatoms.

According to the present invention, the term “hydroxyl” denotes the OHgroup.

According to the present invention, the term “amino” denotes the NH₂group.

According to the present invention, the term “acyl” denotes a formyl ora carbonyl substituted with an alkyl.

According to the present invention, the term “sulphonyl” denotes asulphone substituted with an alkyl.

According to the present invention, the term “lower alkyl” denotes alinear or branched, saturated hydrocarbon-based chain containing from 1to 4 carbon atoms or a linear or branched, unsaturated hydrocarbon-basedchain containing from 2 to 4 carbon atoms.

According to the present invention, the term “alkyl” denotes asubstituted or unsubstituted lower alkyl or higher alkyl.

According to the present invention, the term “substituted lower alkyl”denotes a linear or branched, saturated hydrocarbon-based chaincontaining from 1 to carbon atoms, or a linear or branched, unsaturatedhydrocarbon-based chain containing from 2 to 4 carbon atoms, andsubstituted with one or more halogen atoms or with a hydroxyl, and inparticular, for example, methyl, ethyl, propyl, isopropyl or butyl.

According to the present invention, the term “higher alkyl” denotes alinear or branched, saturated or unsaturated hydrocarbon-based chaincontaining from 5 to 10 carbon atoms.

According to the present invention, the term “substituted higher alkyl”is intended to mean a linear or branched, saturated or unsaturatedhydrocarbon-based chain containing from 5 to 10 carbon atoms andsubstituted with one or more halogen atoms or with a hydroxyl.

According to the present invention, the term “cycloalkylalkyl” denotesan alkyl substituted with a cycloalkyl.

According to the present invention, the term “lower alkoxy” denotes anoxygen atom substituted with a lower alkyl, and in particular, forexample, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

According to the present invention, the term “substituted lower alkoxy”denotes an oxygen atom substituted with a substituted lower alkyl.

According to the present invention, the term “higher alkoxy” denotes anoxygen atom substituted with a higher alkyl.

According to the present invention, the term “substituted higher alkoxy”denotes an oxygen atom substituted with a substituted higher alkyl.

According to the present invention, the term “cycloalkylalkoxy” denotesan oxygen atom substituted with a cycloalkylalkyl.

According to the present invention, the term “acyloxy” denotes an oxygenatom substituted with an acyl.

According to the present invention, the term “aralkyl” denotes an alkylsubstituted with an aryl.

According to the present invention, the term “substituted aralkyl”denotes an alkyl substituted with a substituted aryl.

According to the present invention, the term “halogen atom” denoteschlorine, fluorine, iodine and bromine atoms.

According to the present invention, the term “heterocycle” denotes asaturated or unsaturated, cyclic or bicyclic hydrocarbon-based chaincomprising one or more heteroatoms chosen from O, S and N.

According to the present invention, the term “substituted heterocycle”denotes a saturated or unsaturated, cyclic or bicyclic hydrocarbon-basedchain comprising one or more heteroatoms chosen from O, S and N,substituted with one or more alkyl groups.

According to the present invention, the term “heteroaryl” denotes anaromatic heterocycle.

According to the present invention, the term “substituted heteroaryl”denotes an aromatic heterocycle substituted with one or more alkylgroups.

According to the present invention, the term “heteroaralkyl” denotes analkyl substituted with a heteroaryl.

According to the present invention, the term “substituted heteroaralkyl”denotes an alkyl substituted with a substituted heteroaryl.

According to the present invention, the term “heteroalkyl” denotes analkyl substituted with a heterocycle.

According to the present invention, the term “substituted heteroalkyl”denotes an alkyl substituted with a substituted heterocycle.

According to the present invention, the term “acylamino groups” denotesan amine substituted with an acyl.

According to the present invention, the term “sulphonamide groups”denotes an amine substituted with a sulphonyl group.

Among the compounds of general formula (I) which fall within the contextof the present invention, mention may in particular be made of thefollowing:

-   1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-phenylazetidin-3-yl    ester of butyric acid-   N—[(S)-1-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-1-[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   1-[(S)-2-[(S)-2-benzoyl    amino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-o-tolylazetidin-3-yl    acetate-   1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-yl    ester of butyric acid-   N—[(S)-1-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-1-[(S)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-1-[(S)-2-[3-butoxy-3-(3-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(3,4-dichlorobenzyl)-2-(3-hydroxy-3-phenylazetidin-1-yl)-2-oxoethyl]-3-(1H-imidazol-4-yl)-propionamide-   N—[(S)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)-propionamide-   N—[(S)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-cyclohexylmethyl-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(2,4-dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(S)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-hexyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclopropylmethoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(3-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—{(R)-1-benzyl-2-[3-butoxy-3-(4-fluoro-phenyl)azetidin-1-yl]-2-oxoethyl}-3-(4H-imidazol-2-yl)propionamide-   N—[(R)-1-benzyl-2-(3-butoxy-3-phenylazetidin-1-yl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H[1,2,3]triazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-[1,2,4]triazol-3-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide-   N—{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)-3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-chlorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-fluorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-benzyl-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)acrylamide-   N—[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)-1-(3-trifluoromethylbenzyl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)-1-(4-trifluoromethylbenzyl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(3,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(3,4-difluorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(3-fluorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(2-fluorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(2,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(4-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)pentyramide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2,4-dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide-   N—[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)-propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide    trifluoroacetate-   (S)—N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide-   N-[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclohexylmethoxy-3o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   3-(1H-imidazol-4-yl)-N—{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4-trifluorobutoxyl)azetidin-1-yl]ethylpropionamide-   N—[(R)-2-(3-cyclobutylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide-   N—{(R)-1-(4-methoxybenzyl)-2-[3-(3-methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl}-3-(5-methyl-1H-imidazol-4-ylpropionamide-   3-(1H-imidazol-4-yl)-N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-phenylazetidin-1-yl)ethyl]propionamide-   N—[(R)-2-[3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   3-(1H-imidazol-4-yl)-N—{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)azetidin-1-yl]-2-oxoethyl}propionamide-   N—[(R)-2-[3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   3-(1H-imidazol-4-yl)-N—{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-phenyl-3-(4,4,4-trifluorobutyl)azetidin-1-yl]ethyl}propionamide-   N—[(R)-2-[3-(5-fluoropentyl)-3-phenylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclopropyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclopropylmethyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   (S)-2-hydroxy-3-(1H-imidazol-4-yl)-N-[1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]propionamide-   (S)-2-amino-3-(1H-imidazol-4-yl)-N-[1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)butyramide-   (S)—N-[2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)-2-methanesulphonylaminopropionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide    and also the respective salts and enantiomers thereof.

The compounds of general formula (I) are prepared according to reactionscheme 1 presented below.

According to Scheme 1, the compounds of general formula (IV) can beprepared by coupling between the intermediates of formula (II) and anamino acid of formula (III), the amine function of which is protectedwith a protective group Pg (for example, a Boc, CBz or Fmoc group),under conventional peptide coupling conditions, using for example, ascoupling agent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride or hydroxybenzotriazole or TBTU, and as base,triethylamine or diisopropylethylamine in a solvent such asdichloromethane or dimethylformamide.

The amino acids of general formula (IV) are commercially available orare prepared by methods described in the literature (Williams, R. M.,Synthesis of optically active α-amino acids, Pergamon Press, Oxford,1989).

The compounds of general formula (V) are obtained by deprotection of theamine function of the compounds of general formula (IV), by methodschosen from those known to those skilled in the art. They comprise,inter alia, the use of trifluoroacetic acid or of hydrochloric acid indichloromethane or ethyl acetate, for example, in the case of protectionwith a Boc group, hydrogenation with the appropriate metal intetrahydrofuran or methanol, for example, in the case of protection witha CBz group, and piperidine in acetonitrile, for example, in the case ofprotection with an Fmoc group.

In a final stage, the compounds of general formula (I) are prepared bycoupling between the amine of formula (V) and an acid of formula (VI)under conventional peptide coupling conditions, using for example, ascoupling agent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride or hydroxybenzotriazole or TBTU, and as base,triethylamine or diisopropylethylamine in a solvent such asdichloromethane or dimethylformamide.

The compounds of general formula (VI) are commercially available or areprepared according to the methods described in the literature or knownto those skilled in the art, adapted according to the nature of thesubstituents R4 and R5. Depending on the nature of R4 and R5, Schemes 2,3 and 4 hereinafter present examples of preparation of the compounds ofgeneral formula (VI).

For example, when R5 contains an alkyl substituted with a 1,2,3-triazoleheterocycle, the compound (VI) can be prepared according to Scheme 2:

The compounds of general formula (VIII) are obtained by esterificationof the acid function of the compounds of general formula (VII), bymethods chosen from those known to those skilled in the art. Theycomprise, inter alia, the use of sulphuric acid in methanol, forexample. The compounds of formula (IX) obtained from the compounds offormula (VIII) are prepared by methods described in the literature(Loren J. C., Synlett, 2005, 2847-2850) followed by cleavage in a basicmedium in the presence, for example, of sodium hydroxide in awater/methanol mixture, so as to generate the triazole compounds (VI).

For example, when R5 contains an alkyl substituted with an imidazoleheterocycle, the compound (VI) is prepared according to Scheme 3:

The compounds of general formula (X) are commercially available or areprepared according to the methods described in the literature or knownto those skilled in the art. The compounds of general formula (VI) areobtained, for example, by hydrogenation of the compound (X) in thepresence of a catalyst which may be palladium-on-charcoal in methanol.

For example, when R5 contains an alkyl substituted with a heterocycle,the compound (VI) can be prepared according to Scheme 4:

The compounds of general formula (XVIII) are obtained, for example, byWittig reaction between an ylide (XVII) and a heterocycle substitutedwith an aldehyde (XVI) in the presence of a base, which may be lithiumhexamethyl disilazane in a solvent such as tetrahydrofuran, for example.The compounds of general formula (VI) are obtained, for example, byhydrogenation of the compound (XVIII) in the presence of a catalystwhich may be palladium-on-charcoal in an acidic medium, for example inacetic acid.

The compounds of general formula (II) are prepared according to themethods described in the literature or known to those skilled in theart, adapted according to the nature of the substituents R1 and R2.Schemes 5 and hereinafter present examples of preparation of thecompounds of general formula (II).

For example, when R2 contains an alkoxy chain, the compound (II) can beprepared according to Scheme 5:

The compounds of general formula (XII) are obtained, for example, byaddition of a magnesium halide derived from R1 to the N-boc-azetidinone(XI) (commercial) followed by alkylation of the tertiary alcohol in thepresence of a base which may be sodium hydride, for example, and ahalogenated derivative derived from R2, so as to give the compounds(XIII). The compounds of general formula (II) are obtained bydeprotection of the amine function of the compounds of general formula(XIII), for example in the presence of trifluoroacetic acid or ofhydrochloric acid in dichloromethane, or ethyl acetate.

For example, when R2 contains an alkyl chain, the compound of generalformula (II) is prepared according to Scheme 6:

The compounds of general formula (XV) can be obtained, for example, byaddition of a base such as sodium hydride in the presence of ahalogenated derivative derived from R2. The primary alcohols of generalformula (XIX) are synthesized from the nitrile derivatives (XV) in thepresence of a base, for example sodium hydride and paraformaldehyde. Theprimary alcohol function of the compounds (XIX) is converted to asulphonate in the presence of a base which may be triethylamine or tosylchloride, for example. The azetidine compounds of general formula (II)are synthesized by intramolecular cyclization between an amine functionobtained after reduction of the nitrile function, for example in thepresence of lithium aluminium hydride, and the tosylate function of thecompound of general formula (XX).

According to the present invention, the compounds of general formula (I)that are particularly preferred are those for which:

-   -   R1 represents an aryl, a substituted aryl or a cycloalkyl;    -   R2 represents a hydroxyl, a lower alkyl, a substituted lower        alkyl, a higher alkyl, a substituted higher alkyl, a lower        alkoxy, a substituted lower alkoxy, a higher alkoxy, a        substituted higher alkoxy, or a cycloalkylalkoxy;    -   R3 represents an aralkyl or a substituted aralkyl;    -   R4 represents a heteroaralkyl or a substituted heteroaralkyl;    -   R5 represents a hydrogen or an acylamino; and also the        corresponding salts and enantiomers of the compounds of general        formula (I).

The preferred compounds are:

-   N—[(S)-1-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-1-[(S)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(S)-1-[(S)-2-[3-butoxy-3-(3-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(2,4-dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(3-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-benzyl-2-(3-butoxy-3-phenylazetidin-1-yl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-[1,2,4]triazol-3-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide-   N—{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)-3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-benzyl-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-1-(2,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)pentyramide-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide-   N—[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide    trifluoroacetate-   (S)—N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide-   N—[(R)-2-(3-cyclohexylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide-   3-(1H-imidazol-4-yl)-N—{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4-trifluorobutoxyl)azetidin-1-yl]ethylpropionamide-   N—[(R)-2-(3-cyclobutylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide-   N—{(R)-1-(4-methoxybenzyl)-2-[3-(3-methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl}-3-(5-methyl-1H-imidazol-4-ylpropionamide    and also the respective salts and enantiomers thereof.

According to the present invention, the compounds of general formula (I)that are particularly preferred are those for which:

-   -   R1 represents an aryl radical, a substituted aryl radical or a        cycloalkyl radical;    -   R2 represents a lower alkoxy radical, a higher alkoxy radical, a        cycloalkylalkoxy radical, a lower alkyl radical or a higher        alkyl radical;    -   R3 represents a substituted aralkyl radical;    -   R4 represents a substituted imidazole or an unsubstituted        imidazole;    -   R5 represents hydrogen; and also the corresponding salts and        enantiomers of the compounds of general formula (I).

-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide

-   N—{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)-3-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide,

-   N—[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide

-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide    trifluoroacetate

-   N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide

-   N-[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide

-   N—[(R)-2-(3-cyclohexylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

-   3-(1H-imidazol-4-yl)-N—{(R)-1-(4-methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4-trifluorobutoxyl)azetidin-1-yl]ethylpropionamide

-   N—[(R)-2-(3-cyclobutylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide

-   N—{(R)-1-(4-methoxybenzyl)-2-[3-(3-methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl}-3-(5-methyl-1H-imidazol-4-ylpropionamide    and also the respective salts and enantiomers thereof.

The compounds according to the invention havemelanocortin-receptor-modulating properties. The term“melanocortin-receptor-modulating property” is intended to meanmelanocortin receptor agonist or antagonist properties. This activity onMCRs is measured in a transactivation test and quantified by the 50%effective concentration (EC50), as described in Example 10.

Preferably, the compounds are compounds that at least modulate MCRs,selectively with respect to subtype 1 (MC1R), i.e. they exhibit a ratioof the EC50 MC1R relative to the other MCRs of greater than or equal to10. Preferably, this ratio is greater than or equal to 10,advantageously greater than or equal to 20, and more advantageouslygreater than or equal to 50.

Advantageously, the compounds of the present invention exhibit a 50%effective concentration (EC50) value with respect to the MC1 receptor ofless than or equal to 10 μM, and more particularly less than or equal to1 μM.

The invention is therefore directed towards the use of at least onecompound of general formula (I) as defined above, for the preparation ofa pharmaceutical or cosmetic composition in which said compound has amodulatory activity on one or more melanocortin receptors, and inparticular on subtypes 1, 3, 4 and 5.

In one particular embodiment of the invention, the compounds of generalformula (I) in the present invention have an MC1R-selective activity andare particularly useful in the treatment of pigmentary disorders, and ofinflammatory and immune disorders. Some other compounds of the inventionare MC4R-selective and are particularly useful in the treatment ofeating and metabolism disorders and also neurodegenerative disorders.

The invention also relates to a therapeutic or cosmetic treatment methodcomprising the administration of a pharmaceutical or cosmeticcomposition comprising said compound, as a modulator of one or moremelanocortin receptors, and in particular of subtypes 1, 3, 4 and 5. Inone particular embodiment, the invention also relates to a therapeuticor cosmetic method comprising the administration of a pharmaceutical orcosmetic composition comprising said compound, for treating pigmentarydisorders, and inflammatory and immune disorders. In one particularembodiment of the invention, the compounds are subtype-1-selectivemodulators.

The invention also relates to the use of a compound of general formula(I) as defined above, in the preparation of a medicament for use in thetreatment of disorders associated with a dysfunction of MC1R.

Specifically, the compounds used according to the invention areparticularly suitable for the treatment and/or prevention of thedisorders and/or diseases chosen from:

-   -   inflammatory diseases of the digestive tract, including in        particular the intestines (and particularly the colon in the        case of irritable bowel syndrome, ulcerative colitis or Crohn's        disease); pancreatitis, hepatitis (acute and chronic),        inflammatory pathological conditions of the bladder and        gastritis;    -   inflammatory diseases of the locomotor system, including        rheumatoid arthritis, osteoarthritis, osteoporosis, traumatic        arthritis, post-infectious arthritis, muscle degeneration,        dermatomyositis;    -   inflammatory diseases of the urogenital system, and in        particular glomerulonephritis;    -   inflammatory diseases of the cardiac system, and in particular        pericarditis and myocarditis, and diseases including those for        which inflammation is an underlying element. These diseases        include, but are not limited to, atherosclerosis, transplant        atherosclerosis, peripheral vascular diseases, inflammatory        vascular diseases, intermittent claudication or limping,        restenosis, stroke, transient ischaemic attack, myocardial        ischaemia and myocardial infarction. These compounds may also be        used for treating hypertension, hyperlipidaemia, coronary artery        diseases, unstable angina (or angina pectoris), thrombosis,        platelet aggregation induced by thrombin and/or the consequences        of thrombosis and/or of atheroma plaque formation;    -   inflammatory diseases of the respiratory and ENT system,        including in particular asthma, acute respiratory distress        syndrome, hayfever, allergic rhinitis, and chronic obstructive        pulmonary disease. The compounds according to the invention may        also be used for treating allergies;    -   inflammatory diseases of the central nervous system, and in        particular Alzheimer's disease and any form of dementia,        Parkinson's disease, Creutzfeldt-Jacob disease, multiple        sclerosis, meningitis;    -   inflammatory skin diseases, and in particular urticaria,        scleroderma, contact dermatitis, atopic dermatitis, psoriasis,        ichthyosis, acne and other forms of folliculitis, rosacea and        alopecia;    -   autoimmune diseases, and in particular lupus erythematosus,        thyroid conditions, autoimmune diseases of the adrenal gland and        autoimmune gastritis, vitiligo and alopecia areata;    -   inflammations accompanying bacterial, viral or fungal        infections, in particular tuberculosis, septicaemia, fever, HIV        whatever the location of the infection, herpes, cytomegalovirus,        hepatitis A, B and C;    -   transplant or graft rejection, such as kidneys, liver, heart,        lung, pancreas, bone marrow, cornea, intestines, skin (skin        allograft, homograft and heterograft, etc.).

In addition, these compounds may be used for treating pain, whatever theorigin thereof: post-operative pain, neuromuscular pain, headaches,cancer-related pain, dental pain, osteoarticular pain.

These compounds may be useful for modulating pigmentation, and as aresult for:

-   -   treating diseases with pigmentation disorders, and in particular        benign dermatoses such as vitiligo, albinism, melasma,        lentigines, freckles, melanocytic naevi and all        post-inflammatory pigmentations; and also pigmented tumours such        as melanoma and local metastases (permeation nodules), regional        metastases or systemic metastases thereof;    -   photoprotection against sunlight with the aim of preventing:    -   the harmful effects of sunlight such as actinic erythema, skin        ageing, skin cancers (spinocellular, basocellular and melanoma),        and in particular in diseases where it accelerates onset        (xeroderma pigmentosum, basal cell naevus syndrome, familial        melanoma);    -   photodermatoses due to exogenous photosensitizing agents, and in        particular those caused by contact photosensitizing agents (for        example, furocoumarins, halogenated salicylanilides and        derivatives, and local sulphamides and derivatives) or those        caused by photosensitizing agents via the systemic route (for        example, psoralens, tetracyclines, sulphamides, phenothiazines,        nalidixic acid, tricyclic antidepressants);    -   dermatosis attacks with photosensitivity, and in particular        -   photoaggravated dermatoses (for example, lupus            erythematosus, recurrent herpes, congenital poikilodermal or            telangiectasic conditions with photosensitivity (Bloom            syndrome, Cockayne syndrome, Rothmund-Thomson syndrome),            actinic lichen planus, actinic granuloma, disseminated            superficial actinic porokeratosis, acne rosacea, juvenile            acne, bullous dermatoses, Darier's disease, cutaneous            lymphoma, psoriasis, atopic dermatitis, contact eczema,            follicular mucinosis, erythema multiforme, fixed drug            erythema, lymphocytoma cutis, reticular erythema with            mucinosis, melasma),        -   dermatoses with photosensitivity caused by deficiency of the            protection system with melanin formation or distribution            anomalies (for example, oculocutaneous albinism,            phenylketonuria, anterior hypophyseal insufficiency,            vitiligo, piebaldism) and with DNA repair system deficiency            (for example, xeroderma pigmentosum, Cockayne syndrome),        -   dermatoses with photosensitivity caused by metabolic            anomalies, such as cutaneous porphyrias (for example, late            cutaneous porphyria, mixed porphyrias, erythropoietic            protoporphyria, congenital erythropoietic porphyria            (Gunther's disease), erythropoietic coproporphyria),            pellagra or pellagroid erythemas (for example, pellagra,            pellagroid erythemas and tryptophan metabolism disorders);    -   idiopathic photodermatosis attacks, and in particular PMLE        (polymorphous light eruption), benign summer light eruption,        actinic prurigo, persistent photosensitizations        (actino-reticulosis, chronic actinic dermatosis, photosensitive        eczema), solar urticaria, hydroa vacciniforme, juvenile spring        eruption, solar pruritus),    -   modulating the colour of the skin or of the hair and of body        hairs, and in particular by causing the skin to tan by        increasing melanin synthesis or causing it to bleach by        interfering with melanin synthesis, but also by preventing hair        and body hair turning white or grey (for example canities and        piebaldism);    -   modifying the colour of the hair and of body hairs in cosmetic        indications.

These compounds may be useful for modulating sebaceous function for:

-   -   treating conditions with hyperseborrhoea, and in particular        acne, seborrhoeic dermatitis, greasy skin and greasy hair,        hyperseborrhoea in Parkinson's and epilepsy, and        hyperandrogenism;    -   treating conditions with decreased sebaceous secretion, and in        particular xerosis and all dry skin;    -   regulating benign or malignant sebocyte and sebaceous gland        proliferation;    -   treating inflammatory conditions of the pilosebaceous follicle,        and in particular acne, boils, carbuncles and folliculitis.

The invention also relates to the use of a compound of general formula(I) as defined above, for the preparation of a medicament for use in thetreatment of disorders associated with an MC4R dysfunction.

The compounds of the invention may also be used for treatingneurodegenerative disorders, including depression, anxiety, compulsivedisorders such as obsessive-compulsive disorders, neuroses, psychoses,insomnia and sleep disorder, sleep apnoea, and drug abuse.

These compounds may be used for the treatment of male or female sexualdysfunctions. The male sexual dysfunctions include, but are not limitedto, impotence, loss of libido, and erectile dysfunction.

The female sexual dysfunctions include, but are not limited to, sexualstimulation disorders or disorders related to desire, sexualreceptivity, orgasm, and disturbances of the major points of sexualfunction. The female sexual dysfunctions may also include pain, pretermlabour, dysmenorrhoea, excessive menstruation, and endometriosis.

The compounds according to the invention may also be used for treatingdisorders related to weight but not limited to obesity and anorexia(such as modification or impairment of appetite, spleen metabolism,innocent intake of fats or carbohydrates); diabetes mellitus (throughglucose dose tolerance and/or decreased insulin resistance).

The compounds may also be used for treating cancer, and in particularlung cancer, prostate cancer, colon cancer, breast cancer, ovariancancer and bone cancer, or angiogenesis disorders including theformation or growth of solid tumours.

A subject of the present invention is also a pharmaceutical compositionfor use in particular in the treatment of the abovementioned conditions,and which is characterized in that it comprises, in a pharmaceuticallyacceptable carrier compatible with the method of administration selectedfor said composition, a compound of general formula (I) or an enantiomerthereof or a salt thereof with a pharmaceutically acceptable acid.

The term “pharmaceutically acceptable carrier” is intended to mean amedium compatible with the skin, the mucous membranes and the skinappendages.

The administration of the composition according to the invention may becarried out orally, enterally, parenterally, topically or ocularly.Preferably, the pharmaceutical composition is conditioned in a formsuitable for topical application.

When it is for oral administration, the composition may be in the formof tablets, gel capsules, dragees, syrups, suspensions, solutions,powders, granules, emulsions, suspensions of microspheres or nanospheresor lipid or polymeric vesicles for controlled release. When it is forparenteral administration, the composition may be in the form ofsolutions or suspensions for infusion or for injection.

The compounds according to the invention are generally administeredorally or systemically at a daily dose of approximately 0.01 mg/kg to100 mg/kg of body weight, in 1 or more intakes.

The compounds are used systemically at a concentration generally between0.001% and 10% by weight, preferably between 0.01% and 1% by weight,relative to the total weight of the composition.

When administered topically, the pharmaceutical composition according tothe invention is more particularly for use in the treatment of the skinand the mucous membranes, and may be in liquid, pasty or solid form, andmore particularly in the form of salves, creams, milks, ointments,powders, impregnated pads, syndets, solutions, gels, sprays, foams,suspensions, sticks, shampoos or washing bases. It may also be in theform of suspensions of microspheres or nanospheres or lipid or polymericvesicles or polymeric or gelled patches for controlled release.

The compositions used for topical application have a concentration ofcompound according to the invention of generally between 0.001% and 10%by weight, preferably between 0.01% and 5% by weight, relative to thetotal weight of the composition.

The compounds of general formula (I) according to the invention alsofind use in the cosmetics field, in particular in protection against theharmful aspects of sunlight, for preventing and/or combatingphotoinduced or chronological ageing of the skin and the skinappendages.

A subject of the invention is therefore also a composition comprising,in a cosmetically acceptable carrier, at least one of the compounds ofgeneral formula (I). The term “cosmetically acceptable medium” isintended to mean a medium compatible with the skin, the mucous membranesand the skin appendages.

A subject of the invention is also the cosmetic use of a compositioncomprising at least one compound of general formula (I), for preventingand/or treating the signs of ageing and/or the skin.

A subject of the invention is also the cosmetic use of a compositioncomprising at least one compound of general formula (I) for body or hairhygiene.

The cosmetic composition according to the invention containing, in acosmetically acceptable carrier, a compound of general formula (I), oran enantiomer thereof or a salt thereof with a pharmaceuticallyacceptable acid, may be in particular in the form of a cream, a milk, agel, suspensions of microspheres or nanospheres or lipid or polymericvesicles, impregnated pads, solutions, sprays, foams, sticks, soaps,washing bases or shampoos.

The concentration of compound of general formula (I) in the cosmeticcomposition is preferably between 0.001% and 10% by weight, relative tothe total weight of the composition.

The pharmaceutical and cosmetic compositions as described above may alsocontain inert additives, or even pharmacodynamically active additives asregards the pharmaceutical compositions, or combinations of theseadditives, and in particular:

-   -   wetting agents;    -   flavour enhancers;    -   preservatives such as para-hydroxybenzoic acid esters;    -   stabilizers;    -   moisture regulators;    -   pH regulators;    -   osmotic pressure modifiers;    -   emulsifiers;    -   UV-A and UV-B screening agents;    -   antioxidants, such as α-tocopherol, butylhydroxyanisole or        butylhydroxytoluene, superoxide dismutase, ubiquinol;    -   emollients;    -   moisturizers, such as glycerol, PEG 400, thiamorpholinone and        its derivatives or urea;    -   antiseborrhoeic or anti-acne agents, such as        S-carboxymethylcysteine, S-benzylcysteamine, their salts or        their derivatives, or benzoyl peroxide.

Of course, those skilled in the art will take care to select theoptional compound(s) to be added to these compositions in such a waythat the advantageous properties intrinsically associated with thepresent invention are not, or are not substantially, impaired by theenvisaged addition.

Several examples of obtaining compounds of general formula (I) accordingto the invention and of the biological activity results for thesecompounds will now be given by way of illustration that is in no waylimiting in nature.

The following examples describe the preparation of some compounds inaccordance with the invention. These examples are not limiting andmerely illustrate the present invention. The numbers of the compoundsexemplified refer back to those given in Table I hereinafter, whichillustrates the chemical names and the physical properties of somecompounds according to the invention.

The following abbreviations are used:

-   -   TBTU: N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium        tetrafluoroborate    -   HOBt: 1-hydroxy-1,2,3-benzotriazole    -   EDC: 1-ethyl-(3-dimethylaminopropyl)carbodiimide, hydrochloride    -   BOC: tert-butoxycarbonyl    -   CBz: benzyloxycarbonyl    -   Fmoc: 6-fluorenylmethoxycarbonyl    -   Tos: p-toluenesulphonyl    -   DMF: dimethylformamide    -   DCM: dichloromethane    -   DIEA: diisopropylethylamine

The term “conformers” is given to stereoisomers which convert from oneto the other by rotation around bonds (single bond provided by a doubletof electrons).

Material & Methods

HPLC Methods:

Method A

Column: Gemini 150 × 3 mm, 3 μm UV detector: 220-420 nm Flow rate: 0.5ml/min Solvent A: CH₃CN + 0.05 TFA Solvent B: H₂O + 0.05 TFA Gradient:Time composition  0.0 min A = 5%, B = 95%  5.0 min A = 5%, B = 95% 20.0min A = 95%, B = 5% 30.0 min A = 95%, B = 5%

Method B

Column: Gemini 150 × 3 mm, 3 μm UV detector: 220-420 nm Flow rate: 0.5ml/min Solvent A: CH₃CN + 0.05 TFA Solvent B: H₂O + 0.05 TFA Gradient:Time composition  0.0 min A = 5%, B = 95% 20.0 min A = 90%, B = 10% 30.0min A = 90%, B = 10%

Method C

Column: Atlantis C18 150 × 3.2 mm, 3 μm UV detector: 220-420 nm Flowrate: 0.3 ml/min Solvent A: CH₃CN + 0.1 TFA Solvent B: H₂O + 0.1 TFAGradient: Time composition  0.0 min A = 5%, B = 95%  5.0 min A = 5%, B =95% 25.0 min A = 95%, B = 5% 30.0 min A = 95%, B = 5%

Method D

Column: Gemini 150 × 3 mm, 3 μm UV detector: 220-420 nm Flow rate: 0.5ml/min Solvent A: CH₃CN Solvent B: H₂O + 0.02 TFA Gradient: Timecomposition  0.0 min A = 5%, B = 95% 20.0 min A = 90%, B = 10% 30.0 minA = 90%, B = 10%

Method E

Column: Xbridge phenyl 150 × 2.1 mm, 3.5 μm UV detector: 220-420 nm Flowrate: 1.0 ml/min Solvent A: 95% MeOH/5% water + 25 mM NH₄OAc Solvent B:H₂O + 25 mM NH₄OAc Gradient: Time composition  0.0 min A = 5%, B = 95%20.0 min A = 98%, B = 2% 30.0 min A = 98%, B = 2%

Method F

Column: Xbridge phenyl 250 × 4.6 mm, 5 μm UV detector: 220-420 nm Flowrate: 1.0 ml/min Solvent A: 90% MeOH/10% water + 25 mM NH₄OAc Solvent B:H₂O + 25 mM NH₄OAc Gradient: Time composition  0.0 min A = 5%, B = 95%20.0 min A = 98%, B = 2% 30.0 min A = 98%, B = 2%

Method G

Column: Xbridge phenyl 250 × 4.6 mm, 5 μm UV detector: 220-420 nm Flowrate: 1.0 ml/min Solvent A: 90% MeOH/10% water + 25 mM NH₄OAc Solvent B:H₂O + 25 mM NH₄OAc Gradient: Time composition  0.0 min A = 5%, B = 95%15.0 min A = 98%, B = 2% 30.0 min A = 98%, B = 2%

Method H

Column: Gemini C18 150 × 3 mm, 3 μm UV detector: 220-420 nm Flow rate:0.3 ml/min Solvent A: 94% MeOH/6% water + 10 mM NH₄OAc Solvent B: H₂O +10 mM NH₄OAc Gradient: Time composition  0.0 min A = 5%, B = 95% 10.0min A = 95%, B = 5% 30.0 min A = 95%, B = 5%

Method I

Column: Gemini C18 150 × 3 mm, 3 μm UV detector: 220-420 nm Flow rate:0.3 ml/min Solvent A: H₂O + 0.05% TFA Solvent B: CH₃CN + 0.05% TFAGradient: Time composition  0.0 min A = 95%, B = 5.0% 20.0 min A = 5%, B= 95% 30.0 min A = 5%, B = 95%

Method J

Column: Gemini C18 150 × 3 mm, 3 μm UV detector: 220-420 nm Flow rate:0.5 ml/min Solvent A: MeOH + 0.1% TFA Solvent B: H₂O + 0.02% TFAGradient: Time composition  0.0 min A = 10%, B = 90% 15.0 min A = 95%, B= 5% 30.0 min A = 95%, B = 5%

Method K

Column: Gemini C6-phenyl 150 × 3 mm, 3 μm UV detector: 220-420 nm Flowrate: 0.5 ml/min Solvent A: H₂O + 0.05% TFA Solvent B: CH₃CN + 0.05% TFAGradient: Time composition  0.0 min A = 95%, B = 5% 20.0 min A = 5%, B =95% 30.0 min A = 5%, B = 95%

Method L

Column: Gemini C18 150 × 3 mm, 3 μm UV detector: 220-420 nm Flow rate:0.5 ml/min Solvent A: CH₃CN + 0.1% HCOOH Solvent B: H₂O + 0.1% HCOOHGradient: Time Composition  0.0 min A = 5%, B = 95.0% 10.0 min A = 5%, B= 95% 30.0 min A = 70%, B = 30%

Method M

Column: ThermoHypersil Hypurity C18 150 × 4.6 mm, 5 μm UV detector:220-420 nm Flow rate: 0.5 ml/min Solvent A: H₂O + 0.05% TFA Solvent B:CH₃CN + 0.05% TFA Gradient: Time composition  0.0 min A = 95%, B = 5.0%20.0 min A = 5%, B = 95% 30.0 min A = 5%, B = 95%

Method N

Column: Atlantis T3 150 × 2.1 mm, 3 μm UV detector: 220-420 nm Flowrate: 0.3 ml/min Solvent A: H₂O + 0.05% TFA Solvent B: CH₃CN + 0.05% TFAGradient: Time composition  0.0 min A = 95%, B = 5.0% 20.0 min A = 5%, B= 95% 30.0 min A = 5%, B = 95%

Method O

Column: Atlantis T3 150 × 4.6 mm, 5 μm UV detector: 220-420 nm Flowrate: 0.3 ml/min Solvent A: H₂O + 0.05% TFA Solvent B: CH₃CN + 0.05% TFAGradient: Time composition  0.0 min A = 95%, B = 5.0% 20.0 min A = 5%, B= 95% 30.0 min A = 5%, B = 95%

Method P

Column: Atlantis T3 150 × 4.6 mm, 5 μm UV detector: 190-420 nm Flowrate: 0.25 ml/min Solvent A: H₂O + 0.05% TFA Solvent B: CH₃CN + 0.05%TFA Gradient: Time composition  0.0 min A = 95%, B = 5.0% 20.0 min A =5%, B = 95% 30.0 min A = 5%, B = 95%

Method Q

Column: Atlantis T3 150 × 4.6 mm, 5 μm UV detector: 190-420 nm Flowrate: 0.3 ml/min Solvent A: H₂O + 0.05% TFA Solvent B: CH₃CN + 0.05% TFAGradient: Time composition  0.0 min A = 95%, B = 5.0% 20.0 min A = 5%, B= 95% 30.0 min A = 5%, B = 95%

Method R

Column: Gemini C6-phenyl 150 × 3 mm, 3 μm UV detector: 190-420 nm Flowrate: 0.3 ml/min Solvent A: CH₃CN + 0.05% TFA Solvent B: H₂O + 0.05% TFAGradient: Time composition  0.0 min A = 10%, B = 90% 15.0 min A = 90%, B= 10% 30.0 min A = 90%, B = 10%

Method S

Column: Eclipse XDB C8 150 × 4.6 mm, 5 μm UV detector: 190-420 nm Flowrate: 1 ml/min Solvent A: CH₃CN + 0.1% HCOOH Solvent B: H₂O + 0.1% HCOOHGradient: Time composition  0.0 min A = 10%, B = 90% 20.0 min A = 95%, B= 5% 30.0 min A = 95%, B = 5%

Method T

Column: Gemini C6-phenyl 150 × 3 mm, 3 μm UV detector: 190-420 nm Flowrate: 0.3 ml/min Solvent A: CH₃CN + 0.05% TFA Solvent B: H₂O + 0.05% TFAGradient: Time composition  0.0 min A = 10%, B = 90% 20.0 min A = 90%, B= 10% 30.0 min A = 90%, B = 10%

Method U

Column: Atlantis T3 150 × 4.6 mm, 5 μm UV detector: 190-420 nm Flowrate: 0.3 ml/min Solvent A: CH₃CN + 0.05% TFA Solvent B: H₂O + 0.05% TFAGradient: Time composition  0.0 min A = 10%, B = 90% 20.0 min A = 90%, B= 10% 30.0 min A = 90%, B = 10%

Method V

Column: Xbridge C18 250 × 4.5 mm, 5 μm UV detector: 190-420 nm Flowrate: 1 ml/min Solvent A: CH₃CN + 0.05% TFA Solvent B: H₂O + 0.05% TFAGradient: Time composition  0.0 min A = 10%, B = 90% 25.0 min A = 90%, B= 10% 30.0 min A = 90%, B = 10%

Method W

Column: Xbridge Phenyl 150 × 3 mm, 3 μm UV detector: 190-420 nm Flowrate: 1 ml/min Solvent A: CH₃CN + 0.05% TFA Solvent B: H₂O + 0.05% TFAGradient: Time composition  0.0 min A = 10%, B = 90% 25.0 min A = 95%, B= 10% 30.0 min A = 95%, B = 10%

Method X

Column: Atlantis 150 × 2.1 mm, 3 μm UV detector: 190-420 nm Flow rate:0.3 ml/min Solvent A: CH₃CN + 0.02% TFA Solvent B: H₂O + 0.02% TFAGradient: Time composition  0.0 min A = 2%, B = 98% 20.0 min A = 98%, B= 2% 30.0 min A = 98%, B = 2%

Method Y

Column: Xbridge Phenyl 250 × 4 mm, 3 μm UV detector: 190-420 nm Flowrate: 0.8 ml/min Solvent A: CH₃CN + 5% THF + 0.02% TFA Solvent B: H₂O +0.02% HCOOH Gradient: Time composition  0.0 min A = 2%, B = 98% 20.0 minA = 98%, B = 2% 30.0 min A = 98%, B = 2% 32.0 min A = 2%, B = 98% 40.0min A = 2%, B = 98%

Method Z

Column: Atlantis T3 150 × 2.1 mm, 3 μm UV detector: 190-420 nm Flowrate: 0.3 ml/min Solvent A: CH₃CN + 0.02% TFA Solvent B: H₂O + 0.02% TFAGradient: Time composition  0.0 min A = 5%, B = 95% 20.0 min A = 98%, B= 2% 30.0 min A = 98%, B = 2%

EXAMPLE 1N—[(S)-1-[(S)-2-(3-Butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide(compound No. 3; Table I) 1-1(S)-2-[(S)-2-Benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoicacid

5.07 g (15.8 mmol) of TBTU are added to a solution containing 4.05 g(15.6 mmol) of (S)-2-benzoylamino-3-(1H-imidazol-4-yl)propanoic acid in30 ml of DMF. The reaction medium is left to stir for 15 minutes atambient temperature. 3 g (14.3 mmol) of methyl(S)-2-amino-3-(4-methoxyphenyl)propanoate and 7.5 ml of DIEA in 20 ml ofDMF are added dropwise and stirred at ambient temperature for 4 hours.The reaction is stopped by adding water, and the organic products areextracted with dichloromethane. The organic phase is dried in thepresence of magnesium sulphate. After filtration, the solvents areevaporated off. 6.56 g of a pale yellow solid are obtained and dissolvedin 100 ml of THF. 29 ml of a 1N solution of LiOH are added. The reactionmedium is stirred at ambient temperature for 16 hours. 20 ml of asaturated solution of ammonium chloride are added, followed byextraction with diethyl ether. The aqueous phase is acidified to pH 5with a 1N solution of HCl. The white precipitate obtained is filteredoff and oven-dried under vacuum at 40° C. 5.6 g (12.8 mmol) of(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoicacid are obtained with a yield of 88%.

1-2N—[(S)-1-[(S)-2-(3-Butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide1-2-1 3-Hydroxy-3-phenyl-1-(tert-butoxycarbonyl)-azetidine

3.9 ml (11.7 mmol) of a 3M solution of phenylmagnesium bromide indiethyl ether are added dropwise to a solution, immersed in a bath at−50° C., containing 500 mg (2.92 mmol) of3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium isstirred for 1 hour at −50° C. and hydrolysed by adding a saturatedsolution of ammonium chloride. After a return to ambient temperature, a1N solution of hydrochloric acid is added, followed by extraction withethyl acetate. The organic phase is dried and evaporated to dryness. Thecrude product obtained is purified on silica in a 7/3 heptane/ethylacetate mixture. 253 mg in the form of a white powder are obtained witha yield of 35%.

1-2-2 3-Butoxy-3-phenyl-1-(tert-butoxycarbonyl)-azetidine

A solution of 1 g (4.0 mmol) of3-hydroxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml ofDMF is added dropwise to a suspension of 300 mg of 60% NaH in 3 ml ofDMF, immersed in a bath at 0° C. 2.5 ml of n-iodobutane are addeddropwise. The reaction medium is left to stir at 0° C. for 15 minutesand 72 hours at ambient temperature. The medium is hydrolysed byaddition of a saturated solution of ammonium chloride, followed byextraction with ethyl acetate. The organic phase is dried and evaporatedto dryness. The crude product obtained is purified on silica in a 7/3heptane/ethyl acetate mixture. 500 mg in the form of a light yellow oilare obtained with a yield of 41%.

1-2-3 3-Butoxy-3-phenylazetidine trifluoroacetate

1 ml of trifluoroacetic acid is added to a solution containing 500 mg(1.64 mmol) of 3-butoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidinedissolved in 5 ml of dichloromethane. The reaction medium is stirred atambient temperature for 3 hours and then concentrated. The crude productobtained is purified by silica gel chromatography (eluent 90/10dichloromethane/methanol). 400 mg in the form of a pale yellow powderare obtained with a yield of 76%.

1-3N—[(S)-1-[(S)-2-(3-Butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide

1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution is added to200 mg (0.343 mmol) of(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoicacid. After stirring at ambient temperature for 1 hour, the solvents areevaporated off. The residue obtained is dissolved in 5 ml of DMF, and110 mg (0.343 mmol) of TBTU and 2.37 ml of DIEA are added. The reactionmedium is left to stir for 15 minutes at ambient temperature. 47 mg(0.147 mmol) of 3-butoxy-3-phenylazetidine trifluoroacetate dissolved in5 ml of a 1/4 DCM/DMF solution are added dropwise and stirred at ambienttemperature for 16 hours. A 5% citric acid solution is added, followedby extraction with dichloromethane. The organic phase is washed with asaturated solution of potassium hydrogen carbonate. The organic phase isdried and evaporated to dryness. The crude product obtained is purifiedby silica gel chromatography (eluent 9/1 dichloromethane/methanol). 55mg ofN—[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamideare obtained in the form of a white powder with a yield of 60%.

HPLC: (method A); 2 peaks (mixtures of conformers): retention time:16.44 min and 16.60 min, (34+57)%, M+H: 624.

EXAMPLE 2[1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-yl]ester of butyric acid (compound No. 6; Table I) 2-13-(4-Fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)azetidine

6 ml (11.7 mmol) of a 2M solution of 4-fluorophenylmagnesium bromide indiethyl ether are added dropwise to a solution, immersed in a bath at−50° C., containing 500 mg (2.92 mmol) of3-oxo-1-(tert-butoxycarbonyl)azetidine in 10 ml of THF. The medium isstirred for 1 hour at −50° C. and hydrolysed by addition of a saturatedsolution of ammonium chloride. After a return to ambient temperature, a1N solution of hydrochloric acid is added, followed by extraction withethyl acetate. The organic phase is dried and evaporated to dryness. Thecrude product obtained is purified by silica gel chromatography (eluent7/3 heptane/ethyl acetate). 333 mg in the form of a white powder areobtained with a yield of 43%.

2-2 3-Butyryloxy-3-(4-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine

23 mg (0.188 mmol) of DMAP and 0.03 ml of pyridine are added to asolution containing 50 mg (0.187 mmol) of3-butyryloxy-3-(4-fluorophenyl)-1-(tert-butoxy-carbonyl)azetidine in 1ml of dichloromethane. After stirring at ambient temperature for 10minutes, 0.06 ml of butyric anhydride are introduced. After 3 hours, asaturated solution of ammonium chloride is added, followed by extractionwith dichloromethane. The organic phase is dried and evaporated todryness. The crude product obtained is purified by silica gelchromatography (eluent 7/3 heptane/ethyl acetate). 61 mg in the form ofa colourless oil are obtained with a yield of 97%.

2-3 3-(4-Fluorophenyl)azetidin-3-yl butyrate trifluoroacetate

2 ml of trifluoroacetic acid are added to a solution containing 61 mg(0.181 mmol) of3-hydroxy-3-(4-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine dissolvedin 8 ml of dichloromethane. The reaction medium is stirred at ambienttemperature for 3 hours and then concentrated. The crude productobtained is purified by silica gel chromatography (eluent 90/10dichloromethane/methanol). 40 mg in the form of a pale yellow oil areobtained with a yield of 63%.

2-41-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-ylester of butyric acid

1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution is added to109 mg (0.252 mmol) of(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoicacid (cf. procedure 1-1). After stirring at ambient temperature for 1hour, the solvents are evaporated off. The residue obtained is dissolvedin 5 ml of DMF and 81 mg (0.252 mmol) of TBTU and 1.74 ml of DIEA areadded. The reaction medium is left to stir for 15 minutes at ambienttemperature. 40 mg (0.114 mmol) of 3-(4-fluorophenyl)azetidin-3-ylbutyrate trifluoroacetate dissolved in 5 ml of a 1/4dichloromethane/dimethylformamide solution are added dropwise andstirred at ambient temperature for 16 hours. A 5% citric acid solutionis added, followed by extraction with dichloromethane. The organic phaseis washed with a saturated solution of potassium hydrogen carbonate. Theorganic phase is dried and evaporated to dryness. The crude productobtained is purified by silica gel chromatography (eluent 9/1dichloromethane/methanol). 19 mg of1-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-ylester of butyric acid are obtained in the form of a white powder with ayield of 25%.

HPLC: (method B): 2 peaks (mixtures of conformers): retention time:13.51 min and 13.72 min, (28+55)%, M+H: 656.

EXAMPLE 3N—[(S)-1-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide(compound No. 7; Table I) 3-13-Cyclohexyl-3-hydroxy-1-(tert-butoxy-carbonyl)azetidine

0.5 ml of acetic acid and 40 mg of rhodium on alumina 5% are added to asolution containing 117 mg (0.470 mmol) of3-hydroxy-3-phenyl-1-(tert-butoxy-carbonyl)azetidine (cf. procedure1-2-1) dissolved in 4 ml of methanol. The reaction medium is placed at 4bar of hydrogen and heated at 85° C. for 4 hours. The catalyst isfiltered off and washed with methanol and the solvents are evaporatedoff. 120 mg in the form of a beige powder are obtained with a yield of100%.

3-2 3-Cyclohexylazetidin-3-ol trifluoroacetate

1 ml of trifluoroacetic acid is added to a solution containing 120 mg(0.47 mmol) of 3-cyclohexyl-3-hydroxy-1-(tert-butoxycarbonyl)azetidinedissolved in 3 ml of dichloromethane. The reaction medium is stirred atambient temperature for 1 hour and then concentrated to dryness and usedwithout further purification.

3-3N—[(S)-1-[(S)-2-(3-Cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide

1 ml of a 3/2 dichloromethane/trifluoroacetic acid solution is added to84 mg (0.193 mmol) of(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4-yl)propionylamino]-3-(4-methoxyphenyl)propanoicacid (cf. procedure 1-1). After stirring at ambient temperature for 1hour, the solvents are evaporated off. The residue obtained is dissolvedin 1 ml of DMF, and 79 mg (0.246 mmol) of TBTU and 15 drops of DIEA areadded. 0.235 mmol of 3-cyclohexylazetidin-3-ol trifluoroacetatedissolved in 1 ml of a DCM solution is added dropwise and stirred atambient temperature for 2 hours. A saturated solution of potassiumhydrogen carbonate is added, followed by extraction withdichloromethane. The organic phase is washed with a saturated solutionof potassium hydrogen carbonate. The organic phase is dried andevaporated to dryness. The crude product obtained is purified by silicagel chromatography (eluent 85/15 dichloro-methane/methanol mixture). 35mg ofN—[(S)-1-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamideare obtained in the form of a yellow powder with a yield of 32%.

HPLC: (method B): 2 peaks (mixture of conformers): retention time: 10.68min and 10.94 min, (36+62)%, M+H: 574.

EXAMPLE 4N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide(compound No. 24; Table I) 4-13-Pentyloxy-3-o-tolyl-1-(tert-butoxy-carbonyl)azetidine

A solution of 3.53 g (13.4 mmol) of3-hydroxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine (cf. procedure1-2-1) is added dropwise to a suspension of 1.07 g (26.8 mmol) of 60%NaH in 17 ml of DMF, immersed in a bath at 0° C. 9.0 ml of n-iodopentaneare added dropwise. The reaction medium is left to stir at 0° C. for 15minutes and 24 hours at ambient temperature. The medium is hydrolysed byaddition of a saturated solution of ammonium chloride, followed byextraction with ethyl acetate. The organic phase is dried and evaporatedto dryness. The crude product obtained is purified by silica gelchromatography (eluent 7/3 heptane/ethyl acetate). 3.41 g in the form ofa light yellow oil are obtained with a yield of 76%.

4-2 3-pentoxy-3-phenylazetidine trifluoroacetate

5.5 ml of trifluoroacetic acid are added to a solution containing 3.34 g(10 mmol) of 3-pentoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidinedissolved in 10 ml of dichloromethane. The reaction medium is stirred atambient temperature for 2 hours 30 min and then concentrated. The crudeproduct obtained is purified by silica gel chromatography (eluent 90/10dichloromethane/methanol). 3.5 g in the form of a pale yellow oil areobtained with a yield of 100%.

4-3 tert-butyl[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]carbamate

2.93 g (9.93 mmol) of(R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid aredissolved in 10 ml of DMF. 2.08 g (10.9 mmol) of EDC, 1.47 g (10.9 mmol)of HOBt and a solution of 3.45 g (9.93 mmol) of3-pentoxy-3-phenylazetidine trifluoroacetate in 15 ml of DMF are thenadded. 7 ml (40.2 mmol) of DIEA are added. The reaction medium isstirred at ambient temperature for 2 h 30 and then extracted with ethylacetate. The organic phase is washed with 1N sodium hydroxide and thendried over magnesium sulphate, filtered and evaporated. The crudeproduct obtained is purified by silica gel chromatography (eluent 6/4heptane/ethyl acetate). 2.83 g in the form of a white powder areobtained with a yield of 56%.

4-4(R)-2-Amino-3-(4-methoxyphenyl)-1-(3-pentyloxy-3-o-tolylazetidin-1-yl)propan-1-onetrifluoroacetate

2.81 g (5.5 mmol) of tert-butyl[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]carbamateare solubilized in 10 ml of dichloromethane. The reaction medium iscooled to 0° C. 6.5 ml of trifluoroacetic acid are then introduced.After a return to ambient temperature, the reaction medium is stirredfor 5 hours and then concentrated to dryness. The crude product obtainedis purified by silica gel chromatography (eluent 9/1dichloromethane/methanol). 2.81 g in the form of a white powder areobtained with a yield of 97%.

4-5N—[(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

670 mg (2.08 mmol) of TBTU, 0.8 ml of triethylamine and then 1.0 g (1.91mmol) of(R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyloxy-3-o-tolylazetidin-1-yl)propan-1-onetrifluoroacetate are added to a solution containing 370 mg (2.10 mmol)of desamino-histidine hydrochloride in 15 ml of dimethylformamide. Thereaction medium is stirred at ambient temperature for 21 hours. Thereaction is stopped by adding a 1N solution of sodium hydroxide and thenextraction with dichloromethane is carried out. The organic phases arecombined and dried over sodium sulphate. After filtration, the solventsare evaporated off and the residue is then purified by silica gelchromatography (eluent 90/10 dichloromethane/methanol). 598 mg ofN—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o-tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a white powder with a yield of 59%.

HPLC: (method M); retention time: 18.20 min, 99%, M+H: 533.

EXAMPLE 5N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide(compound No. 26; Table I) 5-1 Methyl(R)-2-amino-3-(4-methoxyphenyl)propanoate

20 ml of sulphuric acid are added, dropwise, over a period of 30minutes, to a solution containing 13 g (66.6 mmol) of(R)-2-amino-3-(4-methoxyphenyl)propionic acid in 150 ml of methanol.After stirring for 24 hours at ambient temperature, the reaction mediumis basified to pH 8-9 by introducing 10N sodium hydroxide and asaturated solution of sodium hydrogen carbonate, followed by extractionwith dichloromethane. The organic phase is dried over sodium sulphate,filtered and evaporated. 12.8 g in the form of a pale yellow oil areobtained with a yield of 92%.

5-2 Methyl(R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoate

35.5 ml of DIEA are added to a solution containing 13.2 g (74.7 mmol) ofdesamino-histidine hydrochloride and 24 g (74.7 mmol) of TBTU in 100 mlof DMF. After stirring for 15 minutes at ambient temperature, 14.2 g(67.9 mmol) of methyl (R)-2-amino-3-(4-methoxyphenyl)-propanoate in 150ml of DMF are added. The reaction medium is left to stir for 16 hoursand then basified to pH=8-9 by introducing 1N sodium hydroxide and asaturated solution of sodium hydrogen carbonate, followed by extractionwith dichloromethane. The organic phase is dried over sodium sulphate,filtered and evaporated. The crude product obtained is purified bysilica gel chromatography (eluent 85/15 dichloromethane/methanol). 11.0g in the form of an orange oil are obtained with a yield of 49%.

5-3(R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoicacid

40 ml of a 1N aqueous solution of lithium hydroxide are added to asolution containing 11.0 g (33.3 mmol) of methyl(R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoatein 100 ml of THF. After stirring for 16 hours, the reaction medium isconcentrated. The residue is purified by silica gel chromatography(eluent 70/30/1 dichloromethane/methanol/triethylamine). 8.4 g in theform of a white powder are obtained with a yield of 79%.

5-4-1 2-Phenylheptanenitrile

5 g (42.7 mmol) of phenylacetonitrile are added dropwise to a suspensionof 2 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30minutes at 0° C., 5.32 ml (42.7 mmol) of bromopentane are addeddropwise. The reaction medium is stirred for 16 hours at ambienttemperature and then treated with ice and extracted with ethyl ether.The organic phase is washed with a saturated aqueous solution of sodiumhydrogen carbonate, dried over sodium sulphate, filtered and evaporatedunder pressure. An orangey-yellow oil is obtained and purified byfractionated distillation under reduced pressure (70-75° C. under 1×10⁻¹mbar). 5.14 g in the form of an orangey oil are obtained with a yield of64%.

5-4-2 2-Hydroxymethyl-2-phenylheptanenitrile

5.14 g (27.4 mmol) of 2-phenylheptanenitrile are added to a suspensionof 1.34 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for30 minutes, 7.6 g (220 mmol) of paraformaldehyde are added portionwise.The reaction medium is left to stir at ambient temperature for 6 hoursand then hydrolysed with ice and extracted with diethyl ether. Theorganic phase is washed with a saturated aqueous solution of sodiumhydrogen carbonate, dried over sodium sulphate, filtered and evaporatedunder pressure. The crude product obtained is purified by silica gelchromatography (eluent 8/2 heptane/ethyl acetate). 4.24 g in the form ofa pale yellow oil are obtained with a yield of 71%.

5-4-3 2-cyano-2-phenylheptyl ester of toluene-4-sulphonic acid

4.1 g (21.5 mmol) of p-toluenesulphonyl chloride and 6 ml oftriethylamine are added to a solution containing 4.24 g (19.5 mmol) of2-hydroxymethyl-2-phenylheptanenitrile in 25 ml of dichloromethane. Thereaction medium is left to stir for 15 hours at ambient temperature andthen treated with a 1N solution of hydrochloric acid and extracted withdichloromethane. The organic phase is dried over sodium sulphate,filtered and evaporated under pressure. A yellow oil is obtained andprecipitated from a 9/1 heptane/diisopropyl ether mixture. Theprecipitate formed is filtered off and rinsed with diisopropyl ether.5.26 g in the form of a beige powder are obtained with a yield of 72%.

5-4-4 3-Pentyl-3-phenylazetidine

600 mg (15.52 mmol) of powdered LiAlH₄ are added carefully to a solutioncontaining 5.26 g (14.15 mmol) of 2-cyano-2-phenylheptyl ester oftoluene-4-sulphonic acid in 25 ml of THF under nitrogen. The reactionmedium is left to stir for 1 hour at ambient temperature and thentreated with an aqueous solution of sodium sulphate. After stirring for30 minute at ambient temperature, the salts formed are filtered off andthe filtrate is evaporated under reduced pressure. The residue is takenup in dichloromethane and washed with a 1N aqueous solution of sodiumhydroxide. The organic phase is dried over sodium sulphate, filtered andevaporated under reduced pressure. 2.90 g in the form of a colourlessoil are obtained and used in the next stage without furtherpurification.

5-4-5N—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide

70 mg (0.345 mmol) of 3-pentyl-3-phenylazetidine and 100 mg (0.315 mmol)of (R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoicacid are solubilized in 1 ml of DMF. 67 mg (0.345 mmol) of EDC and 47 mg(0.345 mmol) of HOBT are added to this solution. The whole is left tostir for 4 hours and is then treated with 1N sodium hydroxide andextracted with dichloromethane. The organic phase is dried over sodiumsulphate, filtered and evaporated under pressure. The crude productobtained is purified by silica gel chromatography (eluent 9/1dichloromethane/methanol). 85 mg ofN—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a white powder with a yield of 49%.

HPLC: (method L); retention time: 22.96 min, 97%, M+H: 503.

EXAMPLE 6N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-[1,2,3]triazol-4-yl)propionamide(compound No. 39; Table I) 6-1 3-(1H-[1,2,3]triazol-4-yl)propanoic acid

39 mg of palladium-on-charcoal at 10% are added to a solution containing390 mg (1.7 mmol) of 3-(1-benzyl-1H[1,2,3]triazol-4-yl)propanoic acid in3 ml of methanol. The reaction mixture is placed under 10 bar ofhydrogen pressure and stirred at 60° C. for 16 hours. After filtrationthrough celite, the solvents are evaporated off and the residue ispurified by silica gel chromatography (eluent 95/5dichloro-methane/methanol). 159.8 mg of3-(1H[1,2,3]triazol-4-yl)propanoic acid are obtained in the form of awhite powder with a yield of 67%.

6-2(R)-2-amino-3-(4-methoxyphenyl)-1-(3-butyloxy-3-o-tolylazetidin-1-yl)propan-1-onehydrochloride

6 ml of a 4N solution of hydrochloric acid in ethyl acetate are added to615 mg (1.24 mmol) of tert-butyl[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate(procedure identical to 4-3). The reaction mixture is stirred at ambienttemperature for 2 hours. The precipitate obtained is filtered off,washed with diethyl ether and then dissolved in methanol, followed byevaporation of the solvents. 441 mg of(R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-onehydrochloride are obtained in the form of a white powder with a yield of82%.

6-3N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H[1,2,3]triazol-4-yl)propionamide

146 mg (0.34 mmol) of(R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-onehydrochloride in 2 ml of dimethylformamide are added to a solution of 47mg (0.34 mmol) of 3-(1H[1,2,3]triazol-4-yl)propanoic acid, 119 mg (0.37mmol) of TBTU and 0.15 ml (1.1 mmol) of triethylamine in 2 ml ofdimethylformamide. The reaction mixture is stirred for 2 hours atambient temperature. The reaction is stopped by adding 10 ml of waterand then extracted with ethyl acetate. The organic phases are combined,washed with a 1N solution of sodium hydroxide and then a saturatedsolution of sodium chloride, and dried over sodium sulphate. Afterfiltration, the solvents are evaporated off and the residue is thenpurified by silica gel chromatography (eluent 90/10 ethylacetate/heptane). 78.6 mg ofN—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H[1,2,3]triazol-4-yl)propionamideare obtained in the form of a white powder with a yield of 45%.

HPLC: (method M); retention time: 19.03 min, 93%, M+H: 520.

EXAMPLE 7N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide(compound No. 41; Table I): 7-1 3-(5-Methyl-3H-imidazol-4-yl)propanoicacid

50 mg of palladium-on-charcoal at 10% are added to 500 mg (2.65 mmol) of3-(5-methyl-3H-imidazol-4-yl)acrylic acid chloride in 10 ml of a 0.5Nsolution of sodium hydroxide. The reaction mixture is placed under 6 barof hydrogen pressure and stirred at 80° C. for 72 hours. After havingfiltered off the catalyst through celite, the residue is acidified to pH2 with hydrochloric acid, concentrated to dryness and taken up inethanol. The insoluble material is filtered off and the filtrate isconcentrated to dryness. 102 mg of3-(5-methyl-3H-imidazol-4-yl)propanoic acid chloride are obtained in theform of a white powder with a yield of 16%.

7-2N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamide

146 mg (0.34 mmol) of(R)-2-amino-3-(4-methoxyphenyl)-1-(3-butyloxy-3-o-tolylazetidin-1-yl)propan-1-onehydrochloride in solution in 2 ml of dimethylformamide are added to asolution of 64 mg (0.34 mmol) of 3-(5-methyl-3H-imidazol-4-yl)propanoicacid chloride, 119 mg (2.34 mmol) of TBTU and 0.15 ml (1.1 mmol) oftriethylamine in 2 ml of dimethylformamide. The reaction mixture isstirred for 2 hours at ambient temperature. The reaction is stopped byadding 10 ml of water and then extracted with ethyl acetate. The organicphases are combined, washed with a 1N solution of sodium hydroxide andthen a saturated solution of sodium chloride, and dried over sodiumsulphate. After filtration, the solvents are evaporated off and theresidue is then purified by silica gel chromatography (eluent 90/10dichloromethane/methanol). 154 mg ofN—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol-4-yl)propionamideare obtained in the form of a white powder with a yield of 86%.

HPLC: (method M); retention time: 17.65 min, 96%, M+H: 533.

EXAMPLE 8N—[(S)-2-(3-Hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide(compound No. 11; Table I) 8-1 3-Hydroxy-3-phenylazetidinetrifluoroacetate

1 ml of trifluoroacetic acid is added to a solution containing 50 mg(0.19 mmol) of tert-butyl 3-hydroxy-3-phenylazetidine-1-carboxylatedissolved in 4 ml of dichloromethane. The reaction medium is stirred atambient temperature for 3 hours and then concentrated. The crude productobtained is purified by silica gel chromatography (eluent 90/10dichloromethane/methanol). 36 mg in the form of a white powder areobtained with a yield of 68%.

8-2N—[(S)-2-(3-Hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamidetrifluoroacetate

2 ml of DMF, 106 mg (0.33 mmol) of TBTU and 1 ml of DIEA are added to105 mg (0.33 mmol) of(R)-2-(3-1H-imidazol-4-ylpropionylamino)-3-(4-methoxyphenyl)propanoicacid. The reaction medium is left to stir for 15 minutes at ambienttemperature. 36 mg (0.13 mmol) of 3-hydroxy-3-phenylazetidinetrifluoroacetate dissolved in 5 ml of a 1/4 DCM/DMF solution are addeddropwise and stirred at ambient temperature for 16 hours. A 5% citricacid solution is added, followed by extraction with dichloromethane. Theorganic phase is washed with a saturated solution of potassium hydrogencarbonate. The organic phase is dried and evaporated to dryness. Thecrude product obtained is purified by silica gel chromatography (eluent9/1 dichloromethane/methanol). 6 mg ofN—[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamidetrifluoroacetate are obtained in the form of a white powder with a yieldof 10%.

HPLC: (method D); retention time: 9.25 min, 89%, M+H: 463.

EXAMPLE 9N—[(R)-2-[3-(4-Fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide(compound No. 38; Table I) 9-1-1 (4-Fluorophenyl)heptanenitrile

5 g (37.0 mmol) of (4-fluorophenyl)acetonitrile are added dropwise to asuspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0° C. Afterstirring for 30 minutes at 0° C., 4.62 mmol (37.0 mmol) of bromopentaneare added dropwise. The reaction medium is stirred for 16 hours atambient temperature and then treated with ice and extracted withdichloromethane. The organic phase is dried over sodium sulphate,filtered and evaporated under pressure. An orangey-yellow oil isobtained and used as it is in the next stage.

9-1-2 2-Hydroxymethyl-2-(4-fluorophenyl)-heptanenitrile

The crude (4-fluorophenyl)heptanenitrile obtained in stage 9-1-1 isadded to a suspension of 1.62 g of 60% NaH in 50 ml of DMF cooled to 0°C. After stirring for 30 minutes, 8.9 g (296 mmol) of paraformaldehydeare added portionwise. The reaction medium is left to stir at ambienttemperature for 3 hours and then hydrolysed with ice and extracted withdichloromethane. The organic phase is dried over sodium sulphate,filtered and evaporated under pressure. The crude product obtained ispurified by silica gel chromatography (eluent 8/2 heptane/ethylacetate). 3.85 g in the form of a pale yellow oil are obtained with ayield of 44%.

9-1-3 2-cyano-2-(4-fluorophenyl)heptyl ester of toluene-4-sulphonic acid

3.43 g (18.0 mmol) of p-toluenesulphonyl chloride and 5 ml oftriethylamine are added to a solution containing 3.85 g (16.4 mmol) of2-hydroxymethyl-2-(4-fluorophenyl)heptanenitrile in 40 ml ofdichloromethane. The reaction medium is left to stir for 15 hours atambient temperature and then treated with a 1N solution of hydrochloricacid and extracted with dichloromethane. The organic phase is dried oversodium sulphate, filtered and evaporated under pressure. A yellow oil isobtained and precipitated from an 8/2 dichloromethane/diisopropyl ethermixture. The precipitate formed is filtered off. 4.4 g in the form of abeige powder are obtained with a yield of 65%.

9-1-4 3-Pentyl-3-(4-fluorophenyl)azetidine

471 mg (12.4 mmol) of powdered LiAlH₄ are added carefully to a solutioncontaining 4.4 g (11.3 mmol) of 2-cyano-2-(4-fluorophenyl)heptyl esterof toluene-4-sulphonic acid in 40 ml of THF under nitrogen. The reactionmedium is left to stir for 1 hour at ambient temperature and thentreated with an aqueous solution of sodium sulphate. After stirring for30 minutes at ambient temperature, the salts formed are filtered off andthe filtrate is evaporated under reduced pressure. The residue is takenup in dichloromethane and washed with a 1N aqueous solution of sodiumhydroxide. The organic phase is dried over sodium sulphate, filtered andevaporated under reduced pressure. 2.02 g in the form of a yellow oilare obtained and used in the next stage without further purification.

9-2 Tert-butyl[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)ethyl]carbamate

606 mg (2.05 mmol) of(R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionic acid and 500mg (2.26 mmol) of 3-pentyl-3-(4-fluoro-phenyl)azetidine are dissolved in10 ml of DMF. 473 mg (2.46 mmol) of EDC, 333 mg (2.46 mmol) of HOBt and0.6 ml (4.5 mmol) of triethylamine are added to this solution. Thereaction medium is stirred at ambient temperature for 5 h and thenextracted with dichloromethane. The organic phase is washed with 1Nsodium hydroxide and then dried over magnesium sulphate, filtered andevaporated. The crude product obtained is purified by silica gelchromatography (eluent 6/4 heptane/ethyl acetate). 780 mg in the form ofa white powder are obtained with a yield of 76%.

9-3(R)-2-Amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)-propan-1-one

780 mg (1.56 mmol) of tert-butyl[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-(4-fluoro-phenyl)azetidin-1-yl)ethyl]carbamateare solubilized in 10 ml of dichloromethane. 4 ml of trifluoroaceticacid are introduced. The reaction medium is stirred for 1 hour and thenconcentrated to dryness. The residue is taken up in a 1N aqueoussolution of sodium hydroxide and extracted with dichloromethane and thenthe resulting product is dried over magnesium sulphate, filtered andevaporated.

590 mg in the form of a colourless resin are obtained with a yield of95%.

9-4N—[(R)-2-[3-(4-Fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

600 mg (1.86 mmol) of TBTU and 0.45 ml of triethylamine are added to asolution containing 330 mg (1.86 mmol) of desamino-histidinehydrochloride in 5 ml of dimethylformamide. After stirring for 15minutes, 590 mg (1.55 mmol) of(R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-(4-fluorophenyl)azetidin-1-yl)-propan-1-onedissolved in 5 ml of dimethylformamide are added. The reaction medium isstirred at ambient temperature for 3 days. The reaction is stopped byadding a 1N solution of sodium hydroxide and then extracted with a 1/1heptane/ethyl acetate mixture. The organic phases are combined and driedover sodium sulphate. After filtration, the solvents are evaporated offand the residue is then purified by silica gel chromatography (eluent85/15 dichloromethane/methanol). 490 mg ofN-[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)-propionamideare obtained in the form of a white powder with a yield of 61%.

HPLC: (method 0); retention time: 15.85 min, 99%, M+H: 521.

EXAMPLE 10N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide(compound No. 62; Table I) 10-1-16-(1-Trityl-1H-imidazol-4-yl)hex-5-enoic acid

13.5 ml (14.3 mmol) of a solution of lithium hexamethyldisilazane at1.06 M in THF are added to 3.27 g (7.38 mmol) of(4-carboxybutyl)triphenyl-phosphonium bromide in suspension in 45 ml ofTHF cooled to −75° C. The reaction medium is stirred at −75° C. for 20minutes and then at 0° C. for 15 minutes. After a return to −75° C.,1.50 g (4.43 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde in suspensionin 15 ml of THF are introduced. After a return to ambient temperature,the reaction medium is stirred for 20 hours and then at 90° C. withmicrowave-heating for 5 minutes. The reaction medium is filtered andconcentrated in a rotary evaporator and then taken up in 1/1heptane/EtOAc. The organic phase is washed with a saturated aqueoussolution of NaHCO₃. The aqueous phase obtained is acidified to pH=5 withan aqueous solution of citric acid at 5% and then extracted with a 1/1heptane/EtOAc mixture. The organic phase is dried over MgSO₄, filteredand concentrated in a rotary evaporator. 0.58 g of6-(1-trityl-1H-imidazol-4-yl)hex-5-enoic acid in the form of a beigepowder are obtained with a yield of 31%.

10-1-2 6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate

2 ml of trifluoroacetic acid are added to 0.58 g (1.37 mmol) of6-(1-trityl-1H-imidazol-4-yl)hex-5-enoic acid in suspension in 8 ml ofdichloromethane. After the solvents have been evaporated off, the oilobtained is purified on a silica column (eluent 8/2 DCM/MeOH). 240 mg of6-(1H-imidazol-4-yl)hex-5-enoic acid trifluoroacetate in the form of ayellow oil are isolated with a yield of 60%.

10-1-3 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetate

4 ml of acetic acid and 80 mg of palladium-on-charcoal at 10% are addedto 218 mg (0.741 mmol) of 6-(1H-imidazol-4-yl)hex-5-enoic acidtrifluoroacetate. The reaction medium is placed under a hydrogenatmosphere at atmospheric pressure. After 13 hours, the reaction mediumis filtered through celite. After the solvents have been evaporated off,175 mg of 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetate in the formof a yellow oil are obtained with a yield of 80%.

10-2N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramide

60 mg (0.186 mmol) of TBTU, 0.1 ml (0.715 mmol) of triethylamine and asolution of 79 mg (0.155 mmol) of2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-onetrifluoroacetate (cf. procedure 4-4) in 1 ml of DMF are added to 55 mg(0.186 mmol) of 6-(1H-imidazol-4-yl)hexanoic acid trifluoroacetatedissolved in 1 ml of DMF. The reaction medium is stirred for 66 hoursand is extracted with a 1/2 heptane/EtOAc mixture and then washed with1N sodium hydroxide. The organic phase is dried over MgSO₄, filtered andconcentrated. The crude product obtained is purified on a silica column(eluent 8/2 DCM/MeOH). 40.8 mg ofN-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)hexyramideare obtained in the form of a white powder with a yield of 47%.

HPLC: (method V); retention time: 18.05 min, 99%, M+H: 561.

EXAMPLE 11N—[(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide(compound No. 64; Table I) 11-1-15-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-ium iodide

720 mg (5.2 mmol) of potassium carbonate and 0.34 ml (5.72 mmol) ofiodomethane are added to a solution of 1 g (2.6 mmol) ofN-1-trityl-desamino-histidine in 10 ml of DMF. The reaction medium isheated at 60° C. for 3 hours. After a return to ambient temperature, thereaction medium is treated with water and acetic acid (to pH 4-5) andextracted with dichloromethane. The organic phase is dried over MgSO₄,filtered and evaporated. The residue obtained is purified by silicachromatography (eluent 8/2 DCM/MeOH). 970 mg of5-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-ium iodideare obtained with a yield of 69%.

11-1-2 Methyl 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate

0.5 ml of trifluoroacetic acid is added to a solution of 200 mg (0.37mmol) of 5-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-iumiodide in 2 ml of dichloromethane. The reaction medium is left to stirovernight at ambient temperature and the solvents are evaporated off.The residue is purified by silica chromatography (eluent 9/1 DCM/MeOH.80 mg of methyl 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetateare obtained with a yield of 76%.

11-1-3 3-(3-Methyl-1H-imidazol-4-yl)propionic acid hydrochloride

2 ml of an aqueous solution of sodium hydroxide at 30% are added to asolution of 320 mg (1.13 mmol) of methyl3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate in 10 ml ofTHF. The reaction medium is stirred at ambient temperature for 16 hoursand then cooled to 0° C., and concentrated hydrochloric acid is addeddropwise until pH 1 is obtained. After filtration, the filtrate isevaporated. 87 mg of 3-(3-methyl-1H-imidazol-4-yl)propionic acidhydrochloride are obtained with a yield of 39%.

11-2N—[(R)-1-(4-Methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamide

0.17 ml (1.23 mmol) of triethylamine is carefully added to a solutioncontaining 87 mg (0.45 mmol) of 3-(3-methyl-1H-imidazol-4-yl)propionicacid hydrochloride and 160 mg (0.49 mmol) of TBTU in 1 ml of DMF. Afterstirring for 60 minutes at ambient temperature, 200 mg (0.32 mmol) of(R)-2-amino-3-(4-methoxyphenyl)-1-(3-pentyl-3-phenylazetidin-1-yl)propan-1-onetrifluoroacetate (cf. procedure 9-3) are added and the reaction mediumis left to stir for three days. The reaction medium is treated with a 2heptane/8 EtOAc mixture and a 1N aqueous solution of sodium hydroxide.The organic phase is dried over MgSO₄, filtered and evaporated. Theresidue obtained is purified by silica chromatography (eluent 9 DCM/1MeOH). 21 mg ofN—[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4-yl)propionamideare obtained with a yield of 9%.

HPLC: (method W); retention time: 18.04 min, 96%, M+H: 517.

EXAMPLE NO. 12N—[(R)-2-(3-Cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide(compound No. 66; Table I) 12-1 3-Cyclohexyl-3-pentylazetidine oxalate

254 mg of rhodium-on-alumina at 5% are added to 652 mg (2.62 mmol) of3-pentyl-3-phenylazetidine oxalate (cf.) in 13 ml of water and 6.5 ml ofTHF. The medium is placed under a hydrogen atmosphere at 6 bar ofpressure and heated at 80° C. After 23 hours, the reaction medium isfiltered through celite and the solvents are evaporated off. 0.43 g of3-cyclohexyl-3-pentylazetidine oxalate is obtained with a yield of 64%.

12-2 tert-Butyl[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate

0.36 g (1.98 mmol) of EDC, 0.25 g (1.85 mmol) of HOBt and 0.51 g (1.73mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propionicacid are added to 0.43 g (1.69 mmol) of 3-cyclohexyl-3-pentylazetidineoxalate dissolved in 8 ml of DMF. After 5 minutes, 0.9 ml (6.5 mmol) oftriethylamine is added. After 1 hour 30 minutes, the reaction medium isextracted with a 1/1 EtOAc/heptane mixture and washed with a solution of1N hydrochloric acid, of 1N sodium hydroxide and of water. The organicphase is dried over MgSO₄, filtered and concentrated. The residue ispurified on a silica column (eluent 6/4 heptane/EtOAc). 0.48 g oftert-butyl[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamatein the form of a colourless oil is obtained with a yield of 59%.

12-3(R)-2-Amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one

2.5 ml of trifluoroacetic acid are added, at 0° C., to 0.48 g (0.99mmol) of tert-butyl[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamatedissolved in 10 ml of dichloromethane. After 2 hours, the solvents areevaporated off. The residue is taken up in dichloromethane and washedwith 1N sodium hydroxide. The organic phases are combined, dried overMgSO₄, filtered and concentrated. 327 mg of(R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphen-yl)propan-1-oneare obtained with a yield of 86%.

12-4N—[(R)-2-(3-Cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

100 mg (0.311 mmol) of TBTU and 0.1 ml (0.715 mmol) of triethylamine areadded to 55 mg (0.311 mmol) of 3-(1H-imidazol-4-yl)propionic acidhydrochloride in 1 ml of DMF. After 10 minutes, 99 mg (0.256 mmol) of(R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-onedissolved in 1 ml of DMF are added. After stirring for 118 hours atambient temperature, the reaction medium is extracted with a 1/2heptane/EtOAc mixture and washed with 1N sodium hydroxide and asaturated sodium chloride solution. The organic phase is dried overMgSO₄, filtered and concentrated. The residue is purified on a silicacolumn (eluent 9/1 DCM/MeOH). 72 mg ofN—[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a white powder, with a yield of 55%.

HPLC: (method Y); retention time: 18.34 min, 98%, M+H: 509.

EXAMPLE 13N—[(R)-2-[3-butoxy-3-(2-fluorophenyl)-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide13.1: 3-(2-Fluorophenyl)-3-hydroxy-1-(tert-butoxy-carbonyl)azetidine

3.1 ml (6.1 mmol) of a 2M solution of isopropylmagnesium chloride intetrahydrofuran are added to a solution of 1.1 g (6.2 mmol) of1-bromo-2-fluorobenzene in 4 ml of tetrahydrofuran, cooled beforehand to−25° C. After stirring for 30 minutes at −25° C., a solution of 0.65 g(3.7 mmol) of 3-oxo-1-(tert-butoxycarbonyl)azetidine in 7.5 ml oftetrahydrofuran is added. The reaction medium is stirred for 30 min andthen a saturated aqueous solution of ammonium chloride is added. Theorganic compounds are extracted with a 1/1 heptane/ethyl acetatemixture. The organic phase is dried over magnesium sulphate and thenfiltered and evaporated. The crude product is purified by silica gelchromatography, elution being carried out with a 5/5 heptane/ethylacetate mixture. 135 mg of3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)-azetidine areobtained in the form of a white solid with a yield of 14%.

13.2: 3-Butoxy-3-(2-fluorophenyl)-1-(tert-butoxy-carbonyl)azetidine

135 mg (0.4 mmol) of3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)azetidine at 80% in2 ml of dimethylformamide are added to a suspension of 65 mg (1.6 mmol)of sodium hydride at 60% in 1.5 ml of dimethylformamide, under nitrogen,at 0° C. After stirring for 20 minutes at 0° C., 0.2 ml (1.5 mmol) ofiodobutane are added. The reaction medium is stirred at ambienttemperature for 1 h 30 and is then hydrolysed with water and with asaturated aqueous solution of ammonium chloride and extracted with a 1/2heptane/ethyl acetate mixture. The organic phases are combined, washedwith water, dried over magnesium sulphate, filtered and evaporated. Thecrude product is purified by silica gel chromatography, elution beingcarried out with an 8/2 heptane/ethyl acetate mixture. 104 mg of3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine areobtained in the form of a yellow oil with a yield of 79%.

13.3: 3-Butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate

1 ml of trifluoroacetic acid is added to a solution containing 104 mg(0.3 mmol) of3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine in 3 ml ofdichloromethane at 0° C. After stirring for 30 minutes, the reactionmedium is evaporated off under a stream of nitrogen. 126 mg of3-butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate are obtained inthe form of a pale yellow oil with a yield of 100%.

13.4: tert-Butyl[(R)-2-[3-butoxy-3-(2-fluorophenyl)-azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate

68 mg of EDC (0.3 mmol), 45 mg (0.3 mmol) of HOBt and 100 mg (0.33 mmol)of Boc-D-methoxyphenylalanine are added successively to 126 mg (0.3mmol) of 3-butoxy-3-(2-fluorophenyl)azetidine trifluoroacetate in 1.5 mlof dimethylformamide under nitrogen. After stirring for 5 minutes, 0.2ml (1.3 mmol) of triethylamine is added. The reaction medium is thenstirred for 23 hours at ambient temperature and extracted with a 1/1ethyl acetate/heptane mixture in the presence of a 1N aqueous solutionof sodium hydroxide. The organic phase is washed with a 1N aqueoussolution of hydrochloric acid and then with water, dried over magnesiumsulphate, filtered and evaporated. 94 mg of tert-butyl[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamateare obtained in the form of a yellow oil with a yield of 58%.

13.5:(R)-2-Amino-1-[3-butoxy-3-(2-fluorophenyl)-azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-onetrifluoroacetate

1 ml of trifluoroacetic acid is added to a solution of 94 mg (0.2 mmol)of tert-butyl[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamatein 10 ml of dichloromethane, cooled beforehand to 0° C. After stirringfor 1 h 30 at ambient temperature, the reaction medium is evaporated offunder a stream of nitrogen. 119 mg of(R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-onetrifluoroacetate are obtained in the form of a yellow oil with a yieldof 100%.

13.6:N—[(R)-2-[3-Butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

81 mg (0.3 mmol) of TBTU and 0.1 ml (0.6 mmol) of triethylamine areadded to a solution of 42 mg (0.25 mmol) of desamino-histidinehydrochloride in 1 ml of dimethylformamide. After stirring for 10minutes, 119 mg (0.2 mmol) of(R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-onetrifluoroacetate are added and the reaction medium is stirred for 64 hat ambient temperature. After extraction with a 1/2 heptane/ethylacetate mixture, the organic phase is washed with 1N aqueous solution ofsodium hydroxide and a saturated aqueous solution of sodium chloride,dried over magnesium sulphate, filtered and evaporated. The crudeproduct is purified by silica gel chromatography, elution being carriedout with a 90/10 dichloromethane/methanol mixture. 59 mg ofN—[(R)-2-[3-butoxy-3-(2-fluoro-phenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a white solid with a yield of 57%.

¹H NMR/DMSO d⁶ 100° C.: δ=0.78 (t, J=7.2-7.6 Hz, 3H); 1.23 (sext,J=6.8-7.2 Hz, 2H); 1.37 (quint, J=6.4-7.6 Hz, 2H); 2.38-2.42 (m, 2H);2.68-2.94 (m, 7H); 3.10 (bt, J=5.6-6.4, 2H); 4.00-4.40 (m, 4H); 4.50 (q,J=7.2-7.6 Hz, 1H); 6.67-6.80 (m, 3H); 7.09-7.24 (m, 4H); 7.30-7.43 (m,4H); 7.70-7.90 (m, 1H).

EXAMPLE 14N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide14.1 Methyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate

1 ml (5.5 mmol) of methyl diethylphosphonoacetate are added to asuspension of 220 mg (5.5 mmol) of sodium hydride at 60% in 5 ml oftetrahydrofuran cooled to 0° C. After stirring for 1 h, 500 mg (4.5mmol) of 1-methyl-1H-imidazole-4-carbaldehyde are added and the mixtureis stirred for 4 hours at ambient temperature and then hydrolysed withwater and extracted with ethyl acetate. The organic phase is washed witha saturated aqueous solution of sodium hydrogen carbonate, dried overmagnesium sulphate, filtered and evaporated. The product obtained isprecipitated from heptane and filtered. 430 mg of methyl(E)-3-(1-methyl-1H-imidazol-4-yl)acrylate are obtained in the form of ayellow powder with a yield of 57%.

14.2 3-(1-Methyl-1H-imidazol-4-yl)propanoic acid hydrochloride

50 mg of palladium-on-charcoal at 10% are added to a solution of 100 mg(0.6 mmol) of methyl (E)-3-(1-methyl-1H-imidazol-4-yl)acrylate in 5 mlof a 1N aqueous solution of sodium hydroxide. The reaction medium isflushed with nitrogen and then stirred under a hydrogen atmosphere for24 h. After filtration through celite, the filtrate is brought back topH 2 with a concentrated aqueous solution of hydrochloric acid, tolueneis added, and the medium is concentrated to dryness. The residueobtained is taken up in acetone and the precipitated salts are filteredoff. The filtrate is concentrated. 160 mg of3-(1-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride are obtainedin the form of a solid with a yield of 32%.

14.3N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamide

84 mg (0.3 mmol) of TBTU and 0.1 ml (0.5 mmol) of triethylamine areadded to a solution of 50 mg (0.3 mmol) of3-(1-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride in 2 ml ofdimethylformamide. After stirring for 1 h at ambient temperature, 90 mg(0.2 mmol) of(R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-onehydrochloride (prepared as described in Example 6.2) are added. Thereaction medium is stirred at ambient temperature for 72 h, extractedwith a 2/8 heptane/ethyl acetate mixture and then washed with a 1Naqueous solution of sodium hydroxide. The organic phase is dried overmagnesium sulphate, filtered and evaporated.

The crude product is purified by silica gel chromatography, elutionbeing carried out with a 97/3 dichloromethane/methanol mixture. 22 mg ofN—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl-1H-imidazol-4-yl)propionamideare obtained in the form of a beige powder with a yield of 23%.

HPLC: (Method U); retention time: 15.28 min, 96.5%, M+H: 533

EXAMPLE 15N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamidetrifluoroacetate 15.1: 2-Benzyloxy-4-methoxybenzaldehyde

160 ml (1.3 mmol) of benzyl bromide and (1.3 mmol) of potassiumcarbonate are added to a solution of 2 g (1.3 mmol) of2-hydroxy-4-methoxybenzaldehyde in 20 ml of acetone. The mixture isstirred at reflux for 6 hours and then evaporated. 50 ml of 1N aqueoussolution of sodium hydroxide are added and the medium is extracted withdichloromethane. The organic phase is dried over magnesium sulphate,filtered and evaporated. The residue obtained is precipitated from 1heptane/ethyl acetate mixture (95/5). 2.75 g of2-benzyloxy-4-methoxybenzaldehyde are obtained in the form of a whitepowder with a yield of 86%.

15.2: Methyl(E)-3-(2-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbonyl)aminoacrylate

1.8 g (5.4 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are added to asolution of 1.8 g (6.2 mmol) of (±)-Boc-α-phosphonoglycine trimethylester in 10 ml of dichloromethane, cooled beforehand to 0° C. Themixture is stirred for 10 minutes at 0° C. and then a solution of 1 g(4.1 mmol) of 2-benzyloxy-4-methoxybenzaldehyde in 5 ml ofdichloromethane is added and the reaction medium is then stirred for 18h at ambient temperature. After the dichloromethane has been evaporatedoff, the residue is taken up in 50 ml of ethyl acetate. The organicphase is washed with a saturated aqueous solution of ammonium chloride,and water, dried over magnesium sulphate, filtered and evaporated. Theresidue obtained is purified by silica gel chromatography (eluent: 70/30heptane/ethyl acetate). 1.5 g of methyl(E)-3-(2-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbonylamino)acrylateare obtained in the form of a beige powder with a yield of 85%.

15.3: Methyl2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)propanoate

350 mg of palladium-on-charcoal at 10% are added to a solutioncontaining 1.5 g (3.5 mmol) of methyl(E)-3-(2-benzyloxy-4-methoxyphenyl)-2-(tert-butoxycarbonylamino)acrylatein 15 ml of methanol. After stirring for hours under a hydrogenatmosphere, the reaction medium is filtered through celite and thefiltrate is evaporated off. 850 mg of methyl2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoate areobtained in the form of a grey powder with a yield of 74%.

15.4: 2-tert-Butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)propanoicacid

5 ml of a 1N aqueous solution of sodium hydroxide are added to asolution of 850 mg (2.6 mmol) of methyl2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoate in10 ml of tetrahydrofuran. The reaction medium is stirred for 4 hours atambient temperature and then a 1N aqueous solution of hydrochloric acidis added until the pH is 1, and the medium is extracted withdichloromethane. The organic phase is dried over magnesium sulphate,filtered and evaporated. 820 mg of2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)propanoic acidare obtained in the form of a beige powder with a quantitative yield.

15.5: 3-butoxy-3-o-tolylazetidine trifluoroacetate

1 ml of trifluoroacetic acid is added to a solution containing 500 mg(1.65 mmol) of3-butoxy-3-o-tolylazetidine-1-(tert-butoxycarbonyl)azetidine dissolvedin 5 ml of dichloromethane. The reaction medium is stirred at ambienttemperature for 3 hours and then concentrated. The crude productobtained is purified by silica gel chromatography (eluent: 90/10dichloromethane/methanol). 400 mg in the form of a pale yellow powderare obtained with a yield of 76%.

15.6: tert-Butyl[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]carbamate

74 mg (0.4 mmol) of EDC and 52 mg (0.4 mmol) of HOBt are added to asolution of 100 mg (0.3 mmol) of2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoic acidin 5 ml of dimethylformamide. The mixture is stirred for 15 min and 107mg (0.3 mmol) of 3-butoxy-3-o-tolylazetidine trifluoroacetate are added.After stirring for a further 15 minutes at ambient temperature, 0.3 ml(1.3 mmol) of diisopropylethylamine is added. The reaction medium isstirred for 2 h, and then 10 ml of a 1N aqueous solution of hydrochloricacid are added and the medium is extracted with ethyl acetate. Theorganic phase is washed with water and then dried over magnesiumsulphate, filtered and evaporated. The residue is filtered throughsilica gel (eluent: 70/30 heptane/ethyl acetate). 220 mg of tert-butyl[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]carbamateare obtained in the form of a yellow oil and are used crude in the nextstage.

15.7:2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(2-hydroxy-4-methoxyphenyl)propan-1-onetrifluoroacetate

1 ml of trifluoroacetic acid is added to 220 mg (0.4 mmol) of tert-butyl[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]carbamatein 2 ml of dichloromethane. After stirring for 1 hour at ambienttemperature, the reaction medium is concentrated under vacuum. 250 mg of2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(2-hydroxy-4-methoxyphenyl)propan-1-onetrifluoroacetate are obtained in the form of a yellow oil with aquantitative yield.

15.8:N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamidetrifluoroacetate

0.25 ml (0.6 mmol) of triethylamine is added to a solution of 90 mg (0.6mmol) of desamino-histidine and 207 mg (0.6 mmol) of TBTU in 2 ml ofdimethylformamide. After stirring for 1 h at ambient temperature, 250 mg(0.4 mmol) of2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(3-hydroxy-4-methoxyphenyl)propan-1-onetrifluoroacetate are added and the mixture is stirred for 72 h atambient temperature. 10 ml of a saturated aqueous solution of sodiumhydrogen carbonate are then poured into the reaction medium, which isextracted with a 20/80 heptane/ethyl acetate mixture. The organic phaseis dried over magnesium sulphate, filtered and concentrated. The productis purified by preparative thin layer chromatography (eluent: 90/10dichloro-methane/methanol). 30 mg ofN-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2-hydroxy-4-methoxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamidetrifluoroacetate are obtained in the form of a beige powder with a yieldof 11%.

HPLC: (Method A1): retention time: 14.39 min, 94.2%, M+H: 535.

EXAMPLE 16(S)—N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide

0.1 ml (0.8 mmol) of triethylamine is added to a solution containing 50mg (0.3 mmol) of (S)-2-hydroxy-3-(1H-imidazol-4-yl)propanoic acid and100 mg (0.3 mmol) of TBTU in 2 ml of dimethylformamide. After stirringfor 1 hour at ambient temperature, 128 mg (0.3 mmol) of(R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-onehydrochloride (described in Example 6.2) are added and the mixture isstirred for 72 h at ambient temperature. A 1N aqueous solution of sodiumhydroxide is added and the medium is extracted with a 20/80heptane/ethyl acetate mixture. The organic phase is dried over magnesiumsulphate, filtered and concentrated. The crude product is purified bypreparative thin layer chromatography (eluent: 90/10dichloro-methane/methanol). 17 mg of(S)—N—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a white powder with a yield of 13%.

¹H NMR/DMSO d⁶ 100° C.: δ=0.78 (t, J=7.2 Hz, 3H); 1.23 (sext, J=7.3 Hz,2H); 1.36 (quint, J=6.7 Hz, 2H); 2.12 (s, 3H); 2.55-2.75 (m, 1H);2.86-2.98 (m, 7H); 3.68 (bs, 3H); 3.90-4.30 (m, 4H); 4.54 (bq, J=6.4 Hz,1H); 5.25-5.45 (m, 1H); 6.55-6.95 (m, 3H); 7.09-7.27 (m, 6H); 7.43 (bs,1H); 7.50-7.65 (m, 1H).

EXAMPLE 17N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)-propionamide17.1: tert-Butyl[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate

205 mg (1.1 mmol) of EDC and then 145 mg (1.1 mmol) of HOBt are added toa solution of 250 mg (0.9 mmol) of(R)-2-tert-butoxycarbonylamino-3-(4-hydroxyphenyl)-propanoic acid in 5ml of dimethylformamide. After stirring for 15 minutes at ambienttemperature, 300 mg (1.1 mmol) of 3-butoxy-3-o-tolylazetidinetrifluoroacetate (described in Example 15.5) and 0.5 ml (3.6 mmol) oftriethylamine are added. The reaction medium is stirred for 2 h atambient temperature and then a 1N aqueous solution of hydrochloric acidis added and the mixture is extracted with ethyl acetate. The organicphase is washed with water, and then dried over magnesium sulphate,filtered and evaporated. The residue is purified by silica gelchromatography, elution being carried out with a 60/40 heptane/ethylacetate mixture. 410 mg of[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamideare obtained with a yield of 90%.

17.2:2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-onetrifluoroacetate

2 ml of trifluoroacetic acid are added to a solution of 410 mg (0.8mmol) of tert-butyl[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamatein 5 ml of dichloromethane. After stirring for 1 hour at ambienttemperature, the solvent is evaporated off. 440 mg of2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-onetrifluoroacetate are obtained with a quantitative yield.

17.3:N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamide

0.35 ml (2.6 mmol) of triethylamine are added to a solution containing225 mg (1.3 mmol) of desamino-histidine hydrochloride and 410 mg (1.3mmol) of TBTU in 5 ml of DMF. After stirring for 1 hour at ambienttemperature, 440 mg (0.9 mmol) of2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-hydroxyphenyl)propan-1-onetrifluoroacetate are added. After stirring for 72 h at ambienttemperature, the reaction medium is treated with a saturated aqueoussolution of sodium hydrogen carbonate and then extracted with a 20/80heptane/ethyl acetate mixture. The organic phase is dried over magnesiumsulphate, filtered and concentrated. The product is purified bypreparative thin layer chromatography (eluent: 90/10dichloro-methane/methanol). 205 mg ofN-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-hydroxybenzyl)-2-oxoethyl]-3-(3H-imidazol-4-yl)propionamideare obtained in the form of a white powder with a yield of 47%.

¹H NMR/DMSO d⁶ 100° C.: δ=0.80 (t, J=7.6 Hz, 3H,); 1.22 (m, 2H); 1.36(quint, J=6.4 Hz, 2H,); 2.23 (s, 3H); 2.40 (t, J=8.8 Hz, 2H); 2.82-2.70(m, 4H); 2.97 (t, J=6.4 Hz, 2H); 4.09 (d, J=10 Hz, 2H); 4.23 (d, J=7.6Hz, 2H); 4.50 (q, J=7.6 Hz, 1H); 6.63 (m, 2H); 6.70 (s, 1H); 6.99 (m,2H); 7.26-7.20 (m, 4H); 7.49 (s, 1H); 7.75 (s, 1H).

EXAMPLE 18N-[1-(3-Butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide18.1: Ethyl 2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride

5 g (18.6 mmol) of ethyl N-(diphenylmethylene)glycinate in solution in20 ml of tetrahydrofuran are added to a solution of 18.7 ml (18.6 mmol)of 1N potassium tert-butoxide in 20 ml of tetrahydrofuran cooled to −70°C. After stirring for 30 minutes, this mixture is added to a solutioncontaining 3.2 g (18.6 mmol) of 4-methoxybenzoyl chloride in 20 ml oftetrahydrofuran at −70° C. One hour after the addition, the reactionmedium is hydrolysed with a 1N aqueous solution of hydrochloric acid andconcentrated. The residue is taken up in water and extracted withdiethyl ether. The organic phase is dried over magnesium sulphate andthe solvent is then evaporated off. 5.5 g of ethyl2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride are obtainedwith a quantitative yield.

18.2: Ethyl2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxopropanoate

4 g (18.3 mmol) of di-tert-butyl dicarbonate and 2.6 ml (18.3 mmol) oftriethylamine are added to 5 g (18.3 mmol) of ethyl2-amino-3-(4-methoxyphenyl)-3-oxopropanoate hydrochloride dissolved in60 ml of tetrahydrofuran at 0° C. After stirring for 3 hours at ambienttemperature, the mixture is treated with water and extracted with ethylacetate. The organic phase is washed with a 1N aqueous solution ofsodium hydrogen sulphate, and water and then dried over magnesiumsulphate, filtered and concentrated. 4.1 g of ethyl2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxopropanoate areobtained in the form of a yellow oil with a yield of 66%.

18.3: Ethyl2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoate

461 mg (0.7 mmol) of sodium borohydride are carefully added to asolution of 4.1 mg (12.2 mmol) of ethyl2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-3-oxopropanoate in 40 mlof ethanol cooled to −78° C. After stirring for 15 minutes, the reactionmedium is hydrolysed with a saturated aqueous solution of ammoniumchloride. The ethanol is evaporated off and the aqueous phase isextracted with dichloromethane. The organic phase is dried overmagnesium sulphate, filtered and concentrated. The residue is purifiedby silica gel chromatography, elution being carried out with a 70/30heptane/ethyl acetate mixture. 3 g of ethyl2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoate areobtained in the form of a yellow oil with a yield of 72%.

18.4: 2-tert-Butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoicacid

15 ml of a 1N aqueous solution of sodium hydroxide are added to asolution containing 3 g (8.4 mmol) of2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)-propanoic acidin 40 ml of tetrahydrofuran. The mixture is stirred for 4 hours atambient temperature, treated with a 1N aqueous solution of hydrochloricacid until the pH is 1, and then extracted with dichloromethane. Theorganic phase is dried over magnesium sulphate, filtered andconcentrated. The residue is precipitated from a 1/1 diethylether/heptane mixture. 2.2 g of2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)-propanoic acidare obtained in the form of a white powder with a yield of 84%.

18.5: tert-Butyl[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]carbamate

740 mg (3.5 mmol) of EDC and 1.2 g (9.6 mmol) of 4-dimethylaminopyridineare added to a solution of 1 g (3.2 mmol) of2-tert-butoxycarbonylamino-3-hydroxy-3-(4-methoxyphenyl)propanoic acid,1.1 g (3.5 mmol) of 3-butoxy-3-o-tolylazetidine trifluoroacetate and 480mg (3.5 mmol) of HOAT in 10 ml of dichloromethane cooled to 0° C. Afterstirring for 24 hours at ambient temperature, the reaction medium istreated with a 1N aqueous solution of sodium hydroxide and thenextracted with ethyl acetate. The organic phase is washed successivelywith a 1N aqueous solution of hydrochloric acid and water, and thendried over magnesium sulphate, filtered and concentrated. The residueobtained is purified by silica gel chromatography (eluent: 60/40heptane/ethyl acetate). 1.4 g of tert-butyl[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]carbamateare obtained in the form of a colourless oil with a yield of 87%.

18.6:2-Amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-onetrifluoroacetate

10 ml of trifluoroacetic acid are added to a solution containing 1.4 g(2.8 mmol) of tert-butyl[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]carbamatein 20 ml of dichloromethane. After stirring for 1 hour at ambienttemperature, the reaction medium is concentrated. 1.5 g of2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-onetrifluoroacetate are obtained in the form of a beige powder with aquantitative yield.

18.7:N-[1-(3-Butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamide

0.2 ml (1.5 mmol) of triethylamine is added to a solution containing 100mg (0.6 mmol) of desamino-histidine hydrochloride and 180 mg (0.6 mmol)of TBTU in 5 ml of dimethylformamide. After stirring for 1 h at ambienttemperature, 200 mg (0.4 mmol) of2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-hydroxy-3-(4-methoxyphenyl)propan-1-onetrifluoroacetate are added. The reaction medium is stirred for 48 h atambient temperature and then treated with a 1N aqueous solution ofsodium hydroxide and extracted with a 20/80 heptane/ethyl acetatemixture. The organic phase is dried over magnesium sulphate, filteredand concentrated. The residue is purified by preparative thin layerchromatography (eluent: 90/10 dichloromethane/methanol). 80 mg ofN-[1-(3-butoxy-3-o-tolylazetidine-1-carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a beige powder with a yield of 39%.

¹H NMR/DMSO d⁶ 100° C.: δ=0.78 (t, J=7.6 Hz, 3H); 1.23 (sext, J=7.3 Hz,2H); 1.37 (quint, J=6.7 Hz, 2H); 2.25 (s, 3H); 2.40-2.50 (m, 2H); 2.75(m, 2H); 3.01 (t,

J=12 Hz, 2H); 3.70-3.80 (bs, 3H); 4.10-4.50 (m, 6H); 4.55 (m, 1H); 4.73(m, 1H); 6.82 (m, 2H); 7.10-7.40 (m, 8H); 7.86 (m, 1H).

EXAMPLE 19N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide19.1: tert-Butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate

2.15 ml (14.5 mmol) of tert-butyl bromoacetate are added dropwise to asolution of 1 g (15.3 mmol) of zinc 20 mesh in 20 ml of tetrahydrofuran,stirred for 15 min with a few drops of trimethylsilane chloride. Afterstirring for 15 minutes at ambient temperature, the temperature of themixture is kept at 50° C. for 1 hour. After a return to ambienttemperature, a solution containing 1.2 g (3.6 mmol) of1-trityl-1H-imidazole-4-carbaldehyde in 10 ml of THF is added. Thereaction medium is stirred for 6 h at ambient temperature, and thentreated with a 1N aqueous solution of hydrochloric acid and extractedwith ethyl acetate. The organic phase is washed successively with asaturated aqueous solution of sodium hydrogen carbonate and then withwater. After drying over magnesium sulphate and filtration, the solventis evaporated off. The residue obtained is precipitated from diisopropylether and filtered off. 1.4 g of tert-butyl3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate are obtained in theform of a white powder with a yield of 84%.

19.2: 3-Hydroxy-3-(1H-imidazol-4-yl)propanoic acid

3 ml of trifluoroacetic acid are added to a solution of 1.4 g (3 mmol)of tert-butyl 3-hydroxy-3-(1-trityl-1H-imidazol-4-yl)propanoate in 7 mlof dichloromethane. After stirring for 4 hours at ambient temperature,the reaction medium is concentrated. 0.5 g of crude product is useddirectly in the next stage.

19.3:N—[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide

0.5 ml (3 mmol) of triethylamine are added to a solution containing 0.5g (3 mmol) of 3-hydroxy-3-(1H-imidazol-4-yl)propanoic acid and 1.0 g (3mmol) of TBTU in 2 ml of dimethylformamide. After stirring for 1 h atambient temperature, 1.5 g (3 mmol) of(R)-2-amino-1-(3-butoxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-onehydrochloride (prepared as described in Example 6.2) are added. Thereaction medium is stirred for 24 h at ambient temperature, treated witha 1N aqueous solution of sodium hydroxide and extracted with a 20/80heptane/ethyl acetate mixture. The organic phase is dried over magnesiumsulphate, filtered and concentrated. The product is purified by silicagel chromatography, elution being carried out with a 97/3dichloromethane/methanol mixture. 72 mg ofN—[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a beige powder with a yield of 5%.

¹H NMR/DMSO d⁶ 100° C.: δ=0.78 (t, J=7.2 Hz, 3H); 1.23(sext, J=7.3 Hz,2H); 1.36 (quint, J=6.7 Hz, 2H); 2.21 (s, 3H); 2.55-2.65 (m, 2H);2.70-2.90 (m, 3H); 2.90-3.00 (m, 2H); 3.68 (bs, 3H); 3.90-4.40 (m, 5H);4.54 (bq, J=7.2 Hz, 1H); 4.92 (bs, 1H); 6.60-6.80 (m, 3H); 7.00-7.30 (m,6H); 7.46 (bs, 1H); 7.81 (bs, 1H).

EXAMPLE 20N—[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide20.1: tert-Butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate

60 ml (60 mmol) of 1M ortho-tolylmagnesium chloride in THF are addeddropwise to a solution of 7.4 g (43 mmol) of tert-butyl3-oxoazetidine-1-carboxylate in 60 ml of tetrahydrofuran cooled to −78°C. After stirring for 1 h at ambient temperature, the mixture ishydrolysed with a saturated aqueous solution of ammonium chloride andthen extracted with ethyl acetate. The organic phase is dried oversodium sulphate, filtered and concentrated. The beige solid obtained ispurified by silica gel chromatography, elution being carried out with a50/50 heptane/ethyl acetate mixture. 8.9 g of tert-butyl3-hydroxy-3-o-tolylazetidine-1-carboxylate are obtained in the form of awhite solid with a yield of 79%.

20.2: tert-Butyl 3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate

1 ml (11.4 mmol) of 1-bromo-2-butyne is added to a suspension of 1.4 g(34.2 mmol) of sodium hydride at 60% in 14 ml of dimethylformamidecooled beforehand to 0° C. After stirring for 1 h, 3 g (11.4 mmol) oftert-butyl 3-hydroxy-3-o-tolylazetidine-1-carboxylate in 20 ml ofdimethylformamide are added dropwise and the reaction mixture is thenstirred for 1 h 30. After hydrolysis with water and with a saturatedaqueous solution of ammonium chloride, the reaction medium is extractedwith a 1/1 heptane/ethyl acetate mixture. The organic phase is driedover sodium sulphate, filtered and concentrated. The residue obtained ispurified by silica gel chromatography, elution being carried out with a80/20 heptane/ethyl acetate mixture. 2.9 g of tert-butyl3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate are obtained in theform of a yellow oil with a yield of 81%.

20.3: 3-But-2-ynyloxy-3-o-tolylazetidine hydrochloride

2.8 g (9 mmol) of tert-butyl3-but-2-ynyloxy-3-o-tolylazetidine-1-carboxylate are solubilised in 40ml (120 mmol) of a 3M solution of hydrochloric acid in ethyl acetate.After stirring for 1 hour 30 minutes at ambient temperature, thereaction medium is concentrated under vacuum. 2.2 g of3-but-2-ynyloxy-3-o-tolylazetidine hydrochloride are obtained in theform of a beige solid with a yield of 96%.

20.4: tert-Butyl[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate

1.9 g (10.2 mmol) of EDC, 1.4 g (10.2 mmol) of HOBt and 3.8 ml (27.2mmol) of triethylamine are added to a solution containing 2.7 g (9.2mmol) of Boc-D-methoxyphenylalanine in 55 ml of dimethylformamide. Afterstirring for 1 h, a solution of 2.2 g (8.7 mmol) of3-but-2-ynyloxy-3-o-tolylazetidine hydrochloride in 35 ml ofdimethylformamide is added to the mixture. The reaction medium is thenstirred for 38 hours at ambient temperature. It is subsequentlyextracted with a 1/1 heptane/ethyl acetate mixture. The organic phase iswashed successively with a 1N aqueous solution of sodium hydroxide andthen with a 1N aqueous solution of hydrochloric acid, dried over sodiumsulphate, filtered and concentrated. The residue obtained is purified bysilica gel chromatography, elution being carried out with a 60/40heptane/ethyl acetate mixture. 1.8 g of tert-butyl[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamateare obtained in the form of a white solid with a yield of 41%.

20.5:(R)-2-Amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one

1.7 g (3.5 mmol) of tert-butyl[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamateare solubilised in 45 ml (135 mmol) of a 3M solution of hydrochloricacid in ethyl acetate. After stirring for 3 h at ambient temperature,the mixture is concentrated. 1.6 g of(R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-oneare obtained in the form of a beige solid with a quantitative yield.

20.6:N—[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide

732 mg (2.3 mmol) of TBTU and 1 ml (7 mmol) of triethylamine are addedto a solution of 408 mg (2.3 mmol) of desamino-histidine hydrochloridein 6 ml of dimethylformamide. After stirring for 10 min, 751 mg (1.8mmol) of(R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-onein 6 ml of dimethylformamide are added. The reaction medium is stirredfor 115 hours at ambient temperature and then a 1N aqueous solution ofsodium hydroxide is added and the medium is extracted with a 1/1heptane/ethyl acetate mixture. The organic phase is dried over sodiumsulphate, filtered and concentrated. The residue obtained is purified bysilica gel chromatography, elution being carried out with a 90/10dichloro-methane/methanol mixture. 362 mg ofN—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamideare obtained in the form of a white solid with a yield of 40%.

¹H NMR/DMSO d⁶ 100° C.: δ=1.74 (bs, 3H); 2.21 (s, 3H); 2.39-2.43 (m,2H); 2.69-3.10 (m, 4H); 3.68 (m, 5H); 4.10-4.40 (m, 4H); 4.52 (q,J=7.2-8.0 Hz, 1H); 6.67-6.85 (m, 3H); 7.05-7.15 (m, 2H); 7.18-7.29 (m,4H); 7.41 (s, 1H); 7.75-7.85 (m, 1H).

EXAMPLE 21N—[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide21.1: 3-(5-Methyl-1H-imidazol-4-yl)propanoic acid hydrochloride

60 mg of palladium-on-charcoal at 10% are added to a solution of 387 mg(1.1 mmol) of (E)-3-(5-methyl-1H-imidazol-4-yl)acrylic acidhydrochloride in a 1/1 tetrahydrofuran/water mixture. The reactionmedium is placed under a hydrogen atmosphere and stirred for 19 h, andthen filtered through celite. The filtrate is concentrated under vacuum.The residue obtained is taken up in a heptane/diisopropyl ether mixturewith stirring for 2 h. The white precipitate formed is filtered off andthen dried. 326 mg of 3-(5-methyl-1H-imidazol-4-yl)propanoic acidhydrochloride are obtained in the form of a white solid with a yield of83%.

21.2:N—[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide

389 mg (1.2 mmol) of TBTU and 0.5 ml (3.7 mmol) of triethylamine areadded to a solution containing 229 mg (1.2 mmol) of3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride in 4 ml ofdimethylformamide. After 5 min, 402 mg (0.9 mmol) of(R)-2-amino-1-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-3-(4-methoxyphenyl)-propan-1-onedissolved in 4 ml of dimethylformamide are added. The reaction medium isthen stirred for 90 h at ambient temperature, and then a 1N aqueoussolution of sodium hydroxide is added and the medium is extracted with a1/1 heptane/ethyl acetate mixture. The organic phase is washed with asaturated aqueous solution of sodium chloride and then dried over sodiumsulphate, filtered and concentrated. The residue obtained is purified bysilica gel chromatography, elution being carried out with an 88/12dichloromethane/methanol mixture. 45 mg ofN—[(R)-2-(3-but-2-ynyloxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamideare obtained in the form of a white solid with a yield of 9%.

¹H NMR/DMSO d⁶ 100° C.: δ=1.74 (s, 3H); 2.06 (s, 3H); 2.21 (s, 3H);2.30-2.45 (m, 2H); 2.55-2.70 (m, 2H); 2.74-3.10 (m, 2H); 3.55-3.80 (m,5H); 4.00-4.45 (m, 4H); 4.50 (bq, J=8.0 Hz, 1H); 6.65-6.85 (m, 2H);7.00-7.15 (m, 2H); 7.15-7.35 (m, 5H); 7.75-7.90 (m, 1H).

Table I illustrates the examples of compounds according to theinvention.

In this table:

-   -   in the “salt” column, TFA represents a compound in        trifluoroacetate form,    -   purity (%) represents the purity of the product, obtained by        HPLC,    -   mass (M+H) represents the mass+1 (hydrogen) derived from the        mass spectrum, associated with the HPLC peak of the expected        product.

TABLE I HPLC Synthesis pathway Purity HPLC retention Mass method used:refer to No. Name Salt (%) time (min) (M + H) used example No. 11-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4- TFA 38 + 51 (20.02 +20.26)* 638 C 2 yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-phenylazetidin-3-yl ester of butyric acid 2N-[(S)-1-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- 34 + 60 (16.61 +16.74)* 638 A 1 methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide 3N-[(S)-1-[(S)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4- 34 + 57 (16.44 +16.80)* 624 A 1 methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide 4N-[(S)-1-[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4- TFA 29 + 62(11.36 + 11.61)* 582 B 1 + 8 methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide 51-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4- TFA 27 + 68 (12.33 +12.53)* 624 B 2 yl)propionylamino]-3-(4- methoxyphenyl)propionyl]-3-o-tolylazetidin-3-yl acetate 61-[(S)-2-[(S)-2-benzoylamino-3-(1H-imidazol-4- 28.55 (13.51 + 13.72)*656 B 2 yl)propionylamino]-3-(4-methoxyphenyl)propionyl]-3-(4-fluorophenyl)azetidin-3-yl ester of butyric acid 7N-[(S)-1-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)- 36 + 62 (10.68 +10.94)* 574 B 3 1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide 8N-[(S)-1-[(S)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1- TFA 38 + 58(12.93 + 13.15)* 642 B 1yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide 9N-[(S)-1-[(S)-2-[3-butoxy-3-(3-fluorophenyl)azetidin-1- TFA 39 + 55(13.11 + 13.33)* 642 B 1yl]-1-(4-methoxybenzyl)-2-oxoethylcarbamoyl]-2-(1H-imidazol-4-yl)ethyl]benzamide Synthesis pathway HPLC HPLC used: Config-Purity retention time Mass method refer to No. Name uration Salt (%)(min) (M + H) used example No. 10N-[(S)-2-(3-cyclohexyl-3-hydroxyazetidin-1-yl)-1-(4- L — 96 9.68 455 D3 + 8 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 11N-[(S)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4- L TFA 89 9.25 463 D 8methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 12N-[(R)-1-(3,4-dichlorobenzyl)-2-(3-hydroxy-3-phenylazetidin- D TFA 9612.1 487 J 8 1-yl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 13N-[(S)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4- L — 95 14.77 491 E 4methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 14N-[(S)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4- L — 9715.65 517 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 15 N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- D —99.8 16.52 517 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 16 N-[(S)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- L —99.2 16.51 519 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 17 N-[(R)-2-(3-ethoxy-3-o-tolylazetidin-1-yl)-1-(4- D —98.7 14.8 491 E 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 18 N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1- D TFA 8417.45 481 E 1 + 8 cyclohexylmethyl-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 19 N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(2,4- DTFA 99 17.68 543 E 1 + 8 dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 20N-[(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4- D — 9615.22 517 F 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 21 N-[(S)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o- L— 99.4 13.59 504 G 4tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 22N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-propoxy-3-o- D — 99.4 13.57 505 G4 tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 23N-[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1-(4- D — 96.2 10.36523 A 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 24N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyloxy-3-o- D — 99 18.2 533 M 4tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 25N-[(R)-2-(3-hexyloxy-3-o-tolylazetidin-1-yl)-1-(4- D — 97 17.1 547 H 4methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 26N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3- D — 97 22.9 503 L 5phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 27N-[(R)-2-(3-butyl-3-phenylazetidin-1-yl)-1-(4- D — 98 15.72 489 I 5methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 28N-[(R)-2-(3-cyclopropylmethoxy-3-phenylazetidin-1-yl)-1-(4- D — 94 14.47503 I 4 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 29N-[(R)-2-(3-hydroxy-3-o-tolylazetidin-1-yl)-1-(4- D TFA 100 13.46 463 K4 + 8 methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide HPLCSynthesis pathway Purity HPLC retention Mass method used: refer to No.Name Salt (%) time (min) (M + H) used example No. 31N-[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1- — 95 15.95 511 I4 (3-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 32N-[(R)-2-[3-butoxy-3-(4-fluorophenyl)azetidin-1-yl]-1- — 99 15.54 511 I4 (4-fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 33N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4- — 93 15.75 493 I 4fluorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 34N-{(R)-1-benzyl-2-[3-butoxy-3-(4-fluoro- — 100 15.42 493 I 4phenyl)azetidin-1-yl]-2-oxoethyl}-3-(4H-imidazol-2- yl)propionamide 35N-[(R)-1-benzyl-2-(3-butoxy-3-phenylazetidin-1-yl)-2- — 91 15.75 475 I 4oxoethyl]-3-(1H-imidazol-4-yl)propionamide 36N-[(R)-2-(3-butoxy-3-phenylazetidin-1-yl)-1-(4- TFA 90 16.93 505 M 4methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 37N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3-o- — 97 16.13 517 N 5tolylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 38N-[(R)-2-[3-(4-fluorophenyl)-3-pentylazetidin-1-yl]-1- — 99 15.85 521 O9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 39N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- — 93 19.03 520 M 6methoxybenzyl)-2-oxoethyl]-3-(1H-[1,2,3]triazol-4- yl)propionamide 40N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- — 98 17.33 534 M 4methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-[1,2,4]triazol-3-yl)propionamide 41N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- — 96 17.65 533 M 7methoxybenzyl)-2-oxoethyl]-3-(5-methyl-3H-imidazol- 4-yl)propionamide 42N-{(R)-1-(4-methoxybenzyl)-2-[3-(2-methoxyphenyl)- — 99 16.37 553 P 93-pentylazetidin-1-yl]-2-oxoethyl}-3-(1H-imidazol-4- yl)propionamide 43N-[(R)-2-[3-(2-fluorophenyl)-3-pentylazetidin-1-yl]-1- — 99 15.65 521 Q9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 44N-[(R)-2-[3-(2-chlorophenyl)-3-pentylazetidin-1-yl]-1- — 98 16.04 537 Q9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 45N-[(R)-1-(4-chlorobenzyl)-2-oxo-2-(3-pentyl-3- — 97 14.85 M = 507 R 9phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 46N-[(R)-1-(4-fluorobenzyl)-2-oxo-2-(3-pentyl-3- — 96 14.39 491 R 9phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 47N-[(R)-1-benzyl-2-oxo-2-(3-pentyl-3-phenylazetidin-1- — 95 14.3 473 R 9yl)ethyl]-3-(1H-imidazol-4-yl)propionamide 48N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)- — 9810.87 517 S 4 2-oxoethyl]-3-(1H-imidazol-4- yl)acrylamide 49N-[(R)-2-[3-(2,4-difluorophenyl)-3-pentylazetidin-1-yl]- — 98 15.89 539T 9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 50N-[(R)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)-1-(3- — 98 16.61 541 T 9trifluoromethylbenzyl)ethyl]-3-(1H-imidazol-4- yl)propionamide 51N-[(R)-2-oxo-2-(3-pentyl-3-phenylazetidin-1-yl)-1-(4- — 98 16.5 541 T 9trifluoromethylbenzyl)ethyl]-3-(1H-imidazol-4- yl)propionamide 52N-[(R)-1-(3,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3- — 96 16.78 M = 541 T9 phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 53N-[(R)-1-(3,4-difluorobenzyl)-2-oxo-2-(3-pentyl-3- — 97 16.02 509 T 9phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 54N-[(R)-2-[3-(3,4-dichlorophenyl)-3-pentylazetidin-1- — 99 17.79 M = 571P 9 yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 55N-[(R)-2-[3-(3-fluorophenyl)-3-pentylazetidin-1-yl]-1- — 96 15.77 521 U9 (4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 56N-[(R)-1-(3-fluorobenzyl)-2-oxo-2-(3-pentyl-3- TFA 98 15.82 491 U 9phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 57N-[(R)-1-(2-fluorobenzyl)-2-oxo-2-(3-pentyl-3- TFA 99 15.76 491 U 9phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 58N-[(R)-1-(2,4-dichlorobenzyl)-2-oxo-2-(3-pentyl-3- — 98 17.3 M = 541 U 9phenylazetidin-1-yl)ethyl]-3-(1H-imidazol-4- yl)propionamide 59N-[(R)-2-[3-(4-dichlorophenyl)-3-pentylazetidin-1-yl]- — 97 16.67 537 U9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 60N-[(R)-2-[3-(2,5-difluorophenyl)-3-pentylazetidin-1-yl]- — 97 18.66 539V 9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 61N-[(R)-2-[3-(2,6-difluorophenyl)-3-pentylazetidin-1-yl]- — 98 18.67 539V 9 1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 62N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- — 99 18.05 561 V 10methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)hexyramide 63N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- TFA 97 17.56 547 V 10methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)pentyramide 64N-[(R)-1-(4-methoxybenzyl)-2-oxo-2-(3-pentyl-3- — 96 18.04 517 W 11phenylazetidin-1-yl)ethyl]-3-(3-methyl-3H-imidazol-4- yl)propionamide 65N-[2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(2,4- — 95 17.49 599 X 10dichlorobenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)hexyramide 66N-[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4- — 98 18.34 509 Y 12methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4- yl)propionamide 67N-[(R)-2-(3-butoxy-3-o-tolylazetidin-1-yl)-1-(4- — 95 15.24 533 Z 11methoxybenzyl)-2-oxoethyl]-3-(3-methyl-3H-imidazol- 4-yl)propionamideHPLC retention HPLC Purity time Mass method No. Name (%) (min) (M + H)used 68 N-[(R)-2-[3-Butoxy-3-(2- — — — —fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol- 4-yl)propionamide 69N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- 96 15.28 533 U(4-methoxybenzyl)-2-oxoethyl]-3-(1-methyl- 1H-imidazol-4-yl)propionamide70 N-[2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1-(2- 94 14.39 535 Thydroxy-4-methoxybenzyl)-2-oxoethyl]-3- (3H-imidazol-4-yl)propionamidetrifluoroacetate 71 (S)-N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)- — —— — 1-(4-methoxybenzyl)-2-oxoethyl]-2-hydroxy-3-(1H-imidazol-4-yl)propionamide 72N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- — — — —(4-hydroxybenzyl)-2-oxoethyl]-3-(3H- imidazol-4-yl)propionamide 73N-[1-(3-Butoxy-3-o-tolylazetidine-1- — — — — carbonyl)-2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-(1H-imidazol-4- yl)propionamide 74N-[(R)-2-(3-Butoxy-3-o-tolylazetidin-1-yl)-1- — — — —(4-methoxybenzyl)-2-oxoethyl]-3-hydroxy-3-(1H-imidazol-4-yl)propionamide 75N-[(R)-2-(3-But-2-ynyl-3-o-tolylazetidin-1-yl)- — — — —1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H- imidazol-4-yl)propionamide 76N-[(R)-2-(3-But-2-ynyloxy-3-o-tolylazetidin-1- — — — —yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4-yl)propionamide 77N-[(R)-2-(3-Cyclohexylmethoxy-3-o- — — — —tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide 783-(1H-Imidazol-4-yl)-N-[(R)-1-(4- — — — —methoxybenzyl)-2-oxo-2-[3-o-tolyl-3-(4,4,4- trifluorobutoxy)azetidin-1-yl]ethylpropionamide 79 N-[(R)-2-(3-Cyclobutylmethoxy-3-o- — — — —tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(5-methyl-1H-imidazol-4- yl)propionamide 80N-[(R)-1-(4-Methoxybenzyl)-2-[3-(3- — — — —methylbut-2-enyloxy)-3-o-tolylazetidin-1-yl]-2-oxoethyl)-3-(5-methyl-1H-imidazol-4- yl)propionamide Synthesis pathwayused: refer to No. ¹H NMR/DMSO D₆ 100° C. Example No. 68 ¹HNMR/DMSO_(D6) 100° C.: δ = 0.78 (t, J = 7.2-7.6 Hz, 3H); 13 1.23 (sext.J = 6.8-7.2 Hz, 2H); 1.37 (quint, J = 6.4-7.6 Hz, 2H); 2.38-2.42 (m,2H); 2.68-2.94 (m, 7H); 3.10 (bt, J = 5.6-6.4, 2H); 4.00-4.40 (m, 4H);4.50 (q, J = 7.2-7.6 Hz, 1H); 6.67-6.80 (m, 3H); 7.09-7.24 (m, 4H);7.30-7.43 (m, 4H); 7.70-7.90 (m, 1H). 69 14 70 15 71 ¹H NMR/DMSO_(D6)100° C.: δ = 1.40 (m, 4H); 2.22 (s, 3H); 16 2.84-2.81 (m, 6H); 2.96 (m,2H); 3.33 (t, J = 6.4 Hz, 2H); 3.68 (m, 3H); 4.08 (d, J = 10 Hz, 2H);4.21 (m, 2H); 4.55 (q, J = 7.2 Hz, 1H); 6.76 (m, 2H); 7.11 (m, 2H);7.27-7.18 (m, 5H); 7.91 (m, 1H); 8.63 (s, 1H). 72 ¹H NMR/DMSO_(D6) 100°C.: δ = 0.78 (t, J = 7.2 Hz, 3H); 17 1.23 (sext, J = 7.3 Hz, 2H); 1.36(quint, J = 6.7 Hz, 2H); 2.12 (s, 3H); 2.55-2.75 (m, 1H); 2.86-2.98 (m,7H); 3.68 (bs, 3H); 3.90-4.30 (m, 4H); 4.54 (bq, J = 6.4 Hz, 1H);5.25-5.45 (m, 1H); 6.55-6.95 (m, 3H); 7.09-7.27 (m, 6H); 7.43 (bs, 1H);7.50-7.65 (m, 1H). 73 ¹H NMR/DMSO_(D6) 100° C.: δ = 0.80 (t, J = 7.6 Hz,3H); 18 1.22 (m, 2H); 1.36 (quint, J = 6.4 Hz, 2H); 2.23 (s, 3H); 2.40(t, J = 8.8 Hz, 2H); 2.82-2.70 (m, 4H); 2.97 (t, J = 6.4 Hz, 2H); 4.09(d, J = 10 Hz, 2H); 4.23 (d, J = 7.6 Hz, 2H); 4.50 (q, J = 7.6 Hz, 1H);6.63 (m, 2H); 6.70 (s, 1H); 6.99 (m, 2H); 7.26-7.20 (m, 4H); 7.49 (s,1H); 7.75 (s, 1H). 74 ¹H NMR/DMSO_(D6) 100° C.: δ = 0.78 (t, J = 7.6 Hz,3H); 19 1.23 (sext, J = 7.3 Hz, 2H); 1.37 (quint, J = 6.7 Hz, 2H); 2.25(s, 3H); 2.40-2.50 (m, 2H); 2.75 (m, 2H); 3.01 (t, J = 12 Hz, 2H);3.70-3.80 (bs, 3H); 4.10-4.50 (m, 6H); 4.55 (m, 1H); 4.73 (m, 1H); 6.82(m, 2H); 7.10-7.40 (m, 8H); 7.86 (m, 1H). 75 ¹H NMR/DMSO_(D6) 100° C.: δ= 0.78 (t, J = 7.2 Hz, 3H); 20 1.23 (sext, J = 7.3 Hz, 2H); 1.36 (quint,J = 6.7 Hz, 2H); 2.21 (s, 3H); 2.55-2.65 (m, 2H); 2.70-2.90 (m, 3H);2.90-3.00 (m, 2H); 3.68 (bs, 3H); 3.90-4.40 (m, 5H); 4.54 (bq, J = 7.2Hz, 1H); 4.92 (bs, 1H); 6.60-6.80 (m, 3H); 7.00-7.30 (m, 6H); 7.46 (bs,1H); 7.81 (bs, 1H). 76 ¹H NMR/DMSO_(D6) 100° C.: δ = 1.74 (bs, 3H); 2.21(s, 3H); 21 2.39-2.43 (m, 2H); 2.69-3.10 (m, 4H); 3.68 (m, 5H);4.10-4.40 (m, 4H); 4.52 (q, J = 7.2-8.0 Hz, 1H); 6.67-6.85 (m, 3H);7.05-7.15 (m, 2H); 7.18-7.29 (m, 4H); 7.41 (s, 1H); 7.75-7.85 (m, 1H).77 δ = 0.79-1.59 (m, 11H); 2.21 (s, 3H); 2.39-2.43 (m, 2H); 8 2.70-2.90(m, 6H); 2.93 (s, 3H); 4.04-4.40 (m, 4H); 4.53 (q, J = 7.2-7.6 Hz, 1H);6.67-6.80 (m, 3H); 7.09-7.26 (m, 7H); 7.40 (s, 1H); 7.77 (s, 1H). 78 δ =1.60 (quintl, 2H); 2.08-2.19 (m, 2H); 2.22 (s, 3H); 8 2.39-2.43 (m, 2H);2.68-2.93 (m, 7H); 3.02-3.06 (m, 2H); 4.07-4.40 (m, 4H); 4.52 (q, J =7.2-7.6 Hz, 1H); 6.65-6.90 (m, 3H); 7.00-7.30 (m, 7H); 7.40 (s, 1H);7.70-7.85 (m, 1H). 79 δ = 1.55 (quintl, J = 7.6-10.8 Hz, 2H); 1.70-1.83(m, 2H); 9 1.88-1.96 (m, 2H); 2.06 (s, 3H); 2.22 (s, 3H); 2.31-2.38 (m,3H); 2.60-2.70 (m, 2H); 2.74-2.80 (m, 1H); 2.80-3.05 (m, 3H); 3.69 (bs,3H); 4.00-4.40 (m, 4H); 4.52 (bq, J = 7.2-7.6 Hz, 1H); 6.70-6.85 (m,2H); 7.05-7.15 (m, 2H); 7.18-7.28 (m, 5H); 7.75-7.85 (m, 1H). 80 δ =1.43 (s, 3H); 1.63 (s, 3H); 2.06 (s, 3H); 2.22 (s, 3H); 9 2.36 (bt, J =6.8-7.2 Hz, 2H); 2.62 (bt, J = 7.2 Hz, 2H); 2.76-3.10 (m, 2H); 3.52 (d,J = 6.8 Hz, 2H); 3.68 (bs, 3H); 4.00-4.45 (m, 4H); 4.52 (q, J = 7.2-7.6Hz, 1H); 5.12 (bt, J = 6.8-8.0 Hz, 1H); 6.65-6.90 (m, 2H); 7.09-7.18 (m,2H); 7.19-7.27 (m, 4H); 7.30 (s, 1H); 7.70-7.85 (m, 1H). (*mixture ofconformers)

EXAMPLE 22 Transactivation Test: Melanocortin Receptors

Cells:

HEK293 lines are transfected with the pCRE-Luc and hMC1R, hMC3R, hMC4Ror hMC5R vectors. The cells are cultured at 37° C., 5% CO₂, in DMEMmedium supplemented with 10% of foetal calf serum.

Principle of the Test:

In the presence of an activator (agonist), the melanocortin receptorwill activate the cAMP pathway which, via the CRE-Luc vector, willresult in the synthesis of luciferase. After the addition of a lysisbuffer containing a luminescent substrate for luciferase, it will bepossible to measure the luminescence proportional to the degree ofactivation or of inhibition of the receptor.

Product Test:

The products are solubilized at 10 mM in DMSO. They are tested in theform of dose-response at a final DMSO concentration of 0.1%. The rangecomprising 10 points and one zero begins at 10 μM with 4-fold dilutions.For testing agonists, the products are tested alone. For determining thebehaviour of antagonists, the products of interest are tested in thepresence of 1 nM NDP-MSH (reference agonist). The cells are seeded at arate of 5000 cells per well (384 well plate) in serum-free DMEM medium,and incubated overnight at 37° C., 5% CO₂.

The products and the reference ligand (NDP-MSH) are added the followingday, and the plates are again incubated for 6 h at 37° C., 5% CO₂. Afterthe addition of lysis buffer containing luciferin, the plates are readon a Top-Count instrument. The results are standardized as % activityusing the 100% (cells+NDP-MSH at 10 nM) and 0% (cells alone) controls.An EC50 is calculated for each product using the XLFit software. Theresults are given in nM.

Example No. EC50 hMC1R (nM) EC50 hMC4R (nM) 1 500 NT 2 30 8000 3 60 40004 250 4000 5 4000 8000 6 2000 8000 7 500 4000 8 120 4000 9 120 1000 108000 IA 11 4000 8000 12 8000 IA 13 2000 15000 14 2000 15000 15 120 400016 2000 15000 17 250 8000 18 8000 8000 19 2000 120 20 120 4000 21 4000IA 22 120 10000 23 60 1000 24 250 4000 25 1000 8000 26 500 4000 27 5008000 28 1000 8000 29 1000 IA 31 500 4000 32 1000 4000 33 500 2000 341000 2000 35 500 2000 36 1000 3000 37 250 2000 38 250 NT 39 8000 2000 408000 500 41 120 1000 42 60 30 43 30 NT 44 30 NT 45 2000 2000 46 10004000 47 500 4000 48 4000 500 49 15 2000 50 1000 500 51 1000 IA 52 2000250 53 1000 4000 54 250 NT 55 120 1000 56 4000 8000 57 1000 4000 58 2000500 59 NT IA 60 120 100 61 120 100 62 4000 500 63 500 500 64 2000 500 65IA 100 66 250 250 67 500 500 68 60 2000 69 1000 8000 70 4000 IA 71 604000 72 2000 IA 73 500 8000 74 250 8000 75 60 4000 76 30 4000 77 1202000 78 120 2000 79 15 1000 80 15 4000 IA: inactive NT: not tested

What is claimed is:
 1. A compound of formula (I)

in which: R1 represents an aryl, a substituted aryl or a cycloalkyl; R2represents a hydrogen atom, a hydroxyl, a lower alkyl, a substitutedlower alkyl, a higher alkyl, a substituted higher alkyl, a cycloalkyl, acycloalkylalkyl, a lower alkoxy, a substituted lower alkoxy, a higheralkoxy, a substituted higher alkoxy, a cycloalkylalkoxy, or an acyloxy;R3 represents an aralkyl or a substituted aralkyl; R4 represents aheteroaralkyl, a substituted heteroaralkyl, a heteroalkyl or asubstituted heteroalkyl; and R5 represents a hydrogen atom, a hydroxyl,an amino, an acylamino or a sulphonamide; or a salt or enantiomer of thecompound of formula (I). 2.-18. (canceled)